The 82 references with contexts in paper V. DOBRONRAVOV A., В. ДОБРОНРАВОВ А. (2011) “CОВРЕМЕННЫЙ ВЗГЛЯД НА ПАТОФИЗИОЛОГИЮ ВТОРИЧНОГО ГИПЕРПАРАТИРЕОЗА: РОЛЬ ФАКТОРА РОСТА ФИБРОБЛАСТОВ 23 И KLOTHO // CURRENT VIEW ON THE PATHOPHYSIOLOGY OF SECONDARY HYPERPARATHYROIDISM: ROLE OF FIBROBLAST GROWTH FACTOR 23 AND KLOTHO” / spz:neicon:nefr:y:2011:i:4:p:11-20

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Bricker NS. On the pathogenesis of the uremic state. An exposition of the ‘trade-off hypothesis’. N Engl J Med 1972;
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    Íàó÷íî-èññëåäîâàòåëüñêèé èíñòèòóò íåôðîëîãèè Ñàíêò-Ïåòåðáóðãñêîãî ãîñóäàðñòâåííîãî ìåäèöèíñêîãî óíèâåðñèòåòà èì. àêàä. È.Ï. Ïàâëîâà, Ðîññèÿ; e-mail: dobronravov@nephrolog.ru, òåë/ôàêñ: +7(812)2346656  1972 ã. N.S. Bricker è ñîàâò.
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    ïðåäëîæèëè äëÿ îáúÿñíåíèÿ ïàòîãåíåçà âòîðè÷íîãî ãèïåðïàðàòèðåîçà (ÂÃÏÒ) òàê íàçûâàåìóþ trade-off òåîðèþ, ñîãëàñíî êîòîðîé âòîðè÷íûé ãèïåðïàðàòèðåîç ÿâëÿåòñÿ ïëàòîé çà ïðåäîòâðàùåíèå ãèïåðôîñôàòåìèè è ãèïîêàëüöèåìèè â óñëîâèÿõ ñíèæåíèÿ ìàññû äåéñòâóþùèõ íåôðîíîâ.

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6 (20): 1093–1099 2. Portale AA, Halloran BP, Murphy MM et al. Oral intake of phosphorus can determine the serum concentration of 1,25dihydroxyvitamin D by determining its production rate in humans. J Clin Invest 1986; 77 (1): 7–12
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     ðåçóëüòàòå äàëüíåéøåé ðàçðàáîòêè ýòîé ãèïîòåçû íà ïðîòÿæåíèè òðåõ äåêàä áûëè ñôîðìèðîâàíû è ðàçâèòû «êëàññè÷åñêèå» ïðåäñòàâëåíèÿ î ìåõàíèçìàõ ðàçâèòèÿ âòîðè÷íîãî ïîâûøåíèÿ ïðîäóêöèè ïàðàòèðåîèäíîãî ãîðìîíà (ÐÒÍ) ïðè ïðîãðåññèðîâàíèè õðîíè÷åñêîé áîëåçíè ïî÷åê (ÕÁÏ)
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    , â êîòîðûõ îñíîâíóþ ðîëü îòâîäèëè ãèïåðôîñôàòåìèè, ãèïîêàëüöèåìèè è ñíèæåíèþ ïðîäóêöèè êàëüöèòðèîëà â ïî÷êàõ, à îñíîâíûìè ðåãóëÿòîðàìè êàëüöèé-ôîñôàòíîãî (ÑàÐ) ãîìåîñòàçà ñ÷èòàëè êàëüöèòðèîë è ÐÒÍ. Ñ óâåëè÷åíèåì îáðàçîâàíèÿ PTH ñâÿçàíû íåñêîëüêî ôèçèîëîãè÷åñêèõ ýôôåêòîâ, íàïðàâëåííûõ íà ïîääåðæàíèå Ñà-Ð-áàëàíñà, ñðåäè êîòîðûõ: ñíèæåíèå óðîâíÿ ôîñôàòà (Ð) â öèðêóëÿöèè çà ñ÷åò ïîäàâëåíèÿ åãî ïî÷å÷í

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Slatopolsky E, Finch J, Denda M et al. Phosphorus restriction prevents parathyroid gland growth. High phosphorus directly stimulates PTH secretion in vitro. J Clin Invest 1996; 97 (11): 2534–2540
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     ðåçóëüòàòå äàëüíåéøåé ðàçðàáîòêè ýòîé ãèïîòåçû íà ïðîòÿæåíèè òðåõ äåêàä áûëè ñôîðìèðîâàíû è ðàçâèòû «êëàññè÷åñêèå» ïðåäñòàâëåíèÿ î ìåõàíèçìàõ ðàçâèòèÿ âòîðè÷íîãî ïîâûøåíèÿ ïðîäóêöèè ïàðàòèðåîèäíîãî ãîðìîíà (ÐÒÍ) ïðè ïðîãðåññèðîâàíèè õðîíè÷åñêîé áîëåçíè ïî÷åê (ÕÁÏ)
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    , â êîòîðûõ îñíîâíóþ ðîëü îòâîäèëè ãèïåðôîñôàòåìèè, ãèïîêàëüöèåìèè è ñíèæåíèþ ïðîäóêöèè êàëüöèòðèîëà â ïî÷êàõ, à îñíîâíûìè ðåãóëÿòîðàìè êàëüöèé-ôîñôàòíîãî (ÑàÐ) ãîìåîñòàçà ñ÷èòàëè êàëüöèòðèîë è ÐÒÍ. Ñ óâåëè÷åíèåì îáðàçîâàíèÿ PTH ñâÿçàíû íåñêîëüêî ôèçèîëîãè÷åñêèõ ýôôåêòîâ, íàïðàâëåííûõ íà ïîääåðæàíèå Ñà-Ð-áàëàíñà, ñðåäè êîòîðûõ: ñíèæåíèå óðîâíÿ ôîñôàòà (Ð) â öèðêóëÿöèè çà ñ÷åò ïîäàâëåíèÿ åãî ïî÷å÷í

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Slatopolsky E. The intact nephron hypothesis: the concept and its implications for phosphate management in CKD-related mineral and bone disorder. Kidney Int 2011; 79 (Suppl 121): S3-S8
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     ðåçóëüòàòå äàëüíåéøåé ðàçðàáîòêè ýòîé ãèïîòåçû íà ïðîòÿæåíèè òðåõ äåêàä áûëè ñôîðìèðîâàíû è ðàçâèòû «êëàññè÷åñêèå» ïðåäñòàâëåíèÿ î ìåõàíèçìàõ ðàçâèòèÿ âòîðè÷íîãî ïîâûøåíèÿ ïðîäóêöèè ïàðàòèðåîèäíîãî ãîðìîíà (ÐÒÍ) ïðè ïðîãðåññèðîâàíèè õðîíè÷åñêîé áîëåçíè ïî÷åê (ÕÁÏ)
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    , â êîòîðûõ îñíîâíóþ ðîëü îòâîäèëè ãèïåðôîñôàòåìèè, ãèïîêàëüöèåìèè è ñíèæåíèþ ïðîäóêöèè êàëüöèòðèîëà â ïî÷êàõ, à îñíîâíûìè ðåãóëÿòîðàìè êàëüöèé-ôîñôàòíîãî (ÑàÐ) ãîìåîñòàçà ñ÷èòàëè êàëüöèòðèîë è ÐÒÍ. Ñ óâåëè÷åíèåì îáðàçîâàíèÿ PTH ñâÿçàíû íåñêîëüêî ôèçèîëîãè÷åñêèõ ýôôåêòîâ, íàïðàâëåííûõ íà ïîääåðæàíèå Ñà-Ð-áàëàíñà, ñðåäè êîòîðûõ: ñíèæåíèå óðîâíÿ ôîñôàòà (Ð) â öèðêóëÿöèè çà ñ÷åò ïîäàâëåíèÿ åãî ïî÷å÷í

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Potts JT. Parathyroid hormone: past and present. J Endocrinol 2005; 187 (3): 311–325
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     òî æå âðåìÿ, PTH ñòèìóëèðóåò RANKL (receptor activator of nuclear factor-κB ligand) â îñòåîáëàñòàõ, êîòîðûé óâåëè÷èâàåò êîëè÷åñòâî îñòåîêëàñòîâ, ïðîöåññû ðåçîðáöèè êîñòè ñ ïîñëåäóþùèì îáðàçîâàíèå è ïîñòóïëåíèå Ð â ñèñòåìíóþ öèðêóëÿöèþ
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    . Ñòèìóëÿöèÿ êèøå÷íîãî âñàñûâàíèÿ Ð îáúÿñíÿëàñü ïîâûøåíèåì àêòèâíîñòè 25(OH)D3 1α-ãèäðîêñèëàçû â ïî÷êàõ â ðåçóëüòàòå äåéñòâèÿ ÐÒÍ è óâåëè÷åíèåì îáðàçîâàíèÿ êàëüöèòðèîëà [äèãèäðîêñèõîëåêàëüöèôåðîëà – 1,25(OH)2D3].

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Kumar R, Thompson JR The regulation of parathyroid hormone secretion and synthesis. J Am Soc Nephrol 2011;22(2):216-224
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    Íà óðîâíå ïàðàùèòîâèäíûõ æåëåç (ÏÙÆ) êàëüöèòðèîë ïîäàâëÿåò ñèíòåç PTH, ïðÿìî âëèÿÿ íà ýêñïðåññèþ åãî ãåíà, à òàêæå îïîñðåäîâàííî – ÷åðåç óâåëè÷åíèå ýêñïðåññèè êàëüöèé-÷óâñòâèòåëüíîãî ðåöåïòîðà (CaSR) è ÷óâñòâèòåëüíîñòè ÏÙÆ ê ýêçîãåííîìó Ñà
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    .  «êëàññè÷åñêîé» ìîäåëè ïåðâè÷íûìè ñòèìóëàìè, çàïóñêàþùèìè ðàçâèòèå ÂÃÏÒ, ñ÷èòàëèñü äâà ñîáûòèÿ: ñíèæåíèå ïðîäóêöèè 1,25(OH)2D3 è óâåëè÷åíèå êîíöåíòðàöèè Ð â öèðêóëÿöèè, êîòîðûå ïðèâîäÿò ê ðàçâèòèþ ãèïîêàëüöèåìèè.

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Denda M, Finch J, Slatopolsky E. Phosphorus accelerates the development of parathyroid hyperplasia and secondary hyperparathyroidism in rats with renal failure. Am J Kidney Dis 1996; 28 (4): 596–602
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     òî æå âðåìÿ, äðóãèì ìîùíûì ôàêòîðîì óâåëè÷åíèÿ ïðîäóêöèè è ñåêðåöèè ÐÒÍ ñ÷èòàëè îñëàáëåíèå ãåíîìíîãî êîíòðîëÿ åãî ïðîäóêöèè â ðåçóëüòàòå äåôèöèòà îáðàçîâàíèÿ êàëüöèòðèîëà â ñêîìïðîìåòèðîâàííîé ïî÷êå, à òàêæå ïðÿìîå âîçäåéñòâèÿ Ð íà ÏÙÆ. Ýôôåêò Ð íà ñåêðåöèþ ÐÒÍ íå çàâèñèò îò 1,25(OH)2D3 è Ñà
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    è, ãëàâíûì îáðàçîì, îïðåäåëÿåòñÿ ïîñòóïëåíèåì Ð èç êèøêè [8]. Âìåñòå ñ òåì, öåëûé ðÿä ñóùåñòâåííûõ ïðîòèâîðå÷èé íå âïîëíå óêëàäûâàëñÿ â êëàññè÷åñêèå ïðåäñòàâëåíèÿ î ïàòîãåíåçå ÂÃÏÒ. Òàê, íàêîïëåííûå âïîñëåäñòâèè êëèíè÷åñêèå äàííûå ïîêàçàëè, ÷òî ïî ìåðå ïðîãðåññèðîâàíèÿ ÕÁÏ ïîâûøåíèå ÐÒÍ îïåðåæàåò ðàçâèòèå çíà÷èìûõ íàðóøåíèé êîíöåíòðàöèè Ñà è Ð â öèðêóëÿöèè, à äîëÿ áîëüíûõ ñ ïîâûøåíèåì ÐÒÍ ñóùåñòâ

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    Õîðîøî èçâåñòíî, ÷òî P ñòèìóëèðóåò ðàçâèòèå ãèïåðïëàçèè ÏÆÙ, íàðÿäó ñ ïîâûøåíèåì ÐÒÍ â ýêñïåðèìåíòàëüíûõ ìîäåëÿõ ÕÁÏ. Íàïðîòèâ îðãàíè÷åíèå Ð ïðèâîäèò ê îáðàòíîìó ýôôåêòó, íåçàâèñèìîìó îò Ca è 1,25(OH)2D3
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    . Ïðîëèôåðàöèÿ êëåòîê ÏÙÆ, êîòîðàÿ ñòàíîâèòñÿ çàìåòíîé óæå ÷åðåç 2 äíÿ ïðèìåíåíèÿ âûñîêîôîñôàòíîé äèåòû, íà ôîíå óðåìèè è âïîñëåäñòâèè óâåëè÷èâàåòñÿ áûñòðûìè òåìïàìè. Ïðîëèôåðàòèâíûå è ãèïåðïëàñòè÷åñêèå ïðîöåññû â ÏÙÆ ïî ìåðå ïðîãðåññèðîâàíèÿ ÂÃÏÒ ñîïðîâîæäàþòñÿ ñíèæåíèåì îñíîâíûõ òèïîâ ðåöåïòîðîâ, ó÷àñòâóþùèõ â ðåãóëÿöèè Ñà-Ð-îáìåíà: ÑaSR è VDR.

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Martin DR, Ritter CS, Slatopolsky E et al. Acute regulation of parathyroid hormone by dietary phosphate. Am J Physiol Endocrinol Metab 2005; 289 (4): E729–E734
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     òî æå âðåìÿ, äðóãèì ìîùíûì ôàêòîðîì óâåëè÷åíèÿ ïðîäóêöèè è ñåêðåöèè ÐÒÍ ñ÷èòàëè îñëàáëåíèå ãåíîìíîãî êîíòðîëÿ åãî ïðîäóêöèè â ðåçóëüòàòå äåôèöèòà îáðàçîâàíèÿ êàëüöèòðèîëà â ñêîìïðîìåòèðîâàííîé ïî÷êå, à òàêæå ïðÿìîå âîçäåéñòâèÿ Ð íà ÏÙÆ. Ýôôåêò Ð íà ñåêðåöèþ ÐÒÍ íå çàâèñèò îò 1,25(OH)2D3 è Ñà [7] è, ãëàâíûì îáðàçîì, îïðåäåëÿåòñÿ ïîñòóïëåíèåì Ð èç êèøêè
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    . Âìåñòå ñ òåì, öåëûé ðÿä ñóùåñòâåííûõ ïðîòèâîðå÷èé íå âïîëíå óêëàäûâàëñÿ â êëàññè÷åñêèå ïðåäñòàâëåíèÿ î ïàòîãåíåçå ÂÃÏÒ. Òàê, íàêîïëåííûå âïîñëåäñòâèè êëèíè÷åñêèå äàííûå ïîêàçàëè, ÷òî ïî ìåðå ïðîãðåññèðîâàíèÿ ÕÁÏ ïîâûøåíèå ÐÒÍ îïåðåæàåò ðàçâèòèå çíà÷èìûõ íàðóøåíèé êîíöåíòðàöèè Ñà è Ð â öèðêóëÿöèè, à äîëÿ áîëüíûõ ñ ïîâûøåíèåì ÐÒÍ ñóùåñòâåííî ïðåâûøàåò äîëè áîëüíûõ ñ ãèïîêàëüöèåìèé è ãèïåðôîñôàòåìè

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Kestenbaum B, Sampson JN, Rudser KD et al. Serum phosphate levels and mortality risk among people with chronic kidney disease. Journal of the American Society of Nephrology. 2005; 16(2):520–528
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    Òàê, íàêîïëåííûå âïîñëåäñòâèè êëèíè÷åñêèå äàííûå ïîêàçàëè, ÷òî ïî ìåðå ïðîãðåññèðîâàíèÿ ÕÁÏ ïîâûøåíèå ÐÒÍ îïåðåæàåò ðàçâèòèå çíà÷èìûõ íàðóøåíèé êîíöåíòðàöèè Ñà è Ð â öèðêóëÿöèè, à äîëÿ áîëüíûõ ñ ïîâûøåíèåì ÐÒÍ ñóùåñòâåííî ïðåâûøàåò äîëè áîëüíûõ ñ ãèïîêàëüöèåìèé è ãèïåðôîñôàòåìèåé
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    . Êðîìå òîãî, óáåäèòåëüíî ïîêàçàíî, ÷òî êîíöåíòðàöèÿ Ð â öèðêóëÿöèè îñòàåòñÿ ó áîëüøèíñòâà áîëüíûõ â íîðìàëüíûõ ïðåäåëàõ, âïëîòü äî ñóùåñòâåííîãî ñíèæåíèÿ ÑÊÔ, ñîîòâåòñòâóþùåãî ÕÁÏ IV ñòàäèè [9–11].

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    ÕÁÏ ïîâûøåíèå ÐÒÍ îïåðåæàåò ðàçâèòèå çíà÷èìûõ íàðóøåíèé êîíöåíòðàöèè Ñà è Ð â öèðêóëÿöèè, à äîëÿ áîëüíûõ ñ ïîâûøåíèåì ÐÒÍ ñóùåñòâåííî ïðåâûøàåò äîëè áîëüíûõ ñ ãèïîêàëüöèåìèé è ãèïåðôîñôàòåìèåé [9]. Êðîìå òîãî, óáåäèòåëüíî ïîêàçàíî, ÷òî êîíöåíòðàöèÿ Ð â öèðêóëÿöèè îñòàåòñÿ ó áîëüøèíñòâà áîëüíûõ â íîðìàëüíûõ ïðåäåëàõ, âïëîòü äî ñóùåñòâåííîãî ñíèæåíèÿ ÑÊÔ, ñîîòâåòñòâóþùåãî ÕÁÏ IV ñòàäèè
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    . Ïî ìåðå ïðîãðåññèðîâàíèÿ ÕÁÏ ñûâîðîòî÷íàÿ êîíöåíòðàöèÿ è îáùåãî, è èîíèçèðîâàííîãî Ñà ïðè íàëè÷èè íåñóùåñòâåííûõ äåâèàöèé îñòàåòñÿ â íîðìàëüíûõ ïðåäåëàõ áåç ÿâíîãî ñíèæåíèÿ, âïëîòü äî ðàçâèòèÿ ÕÁÏ V ñòàäèè [9].

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    Ïî ìåðå ïðîãðåññèðîâàíèÿ ÕÁÏ ñûâîðîòî÷íàÿ êîíöåíòðàöèÿ è îáùåãî, è èîíèçèðîâàííîãî Ñà ïðè íàëè÷èè íåñóùåñòâåííûõ äåâèàöèé îñòàåòñÿ â íîðìàëüíûõ ïðåäåëàõ áåç ÿâíîãî ñíèæåíèÿ, âïëîòü äî ðàçâèòèÿ ÕÁÏ V ñòàäèè
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    . Ñëåäîâàòåëüíî, ãèïîêàëüöèåìèÿ íå ìîæåò ñ÷èòàòüñÿ ñóùåñòâåííûì ôàêòîðîì óâåëè÷åíèå ñåêðåöèè ÐÒÍ, ïî êðàéíåé ìåðå, íà ïðåääèàëèçíûõ ñòàäèÿõ ÕÁÏ. Âîçìîæíî, ÷òî ñåêðåöèÿ ÐÒÍ èçìåíÿåòñÿ â ðåçóëüòàòå ñäâèãà «óñòàíîâî÷íîé òî÷êè» äëÿ àêòèâàöèè CaSR â ñòîðîíó áîëüøèõ êîíöåíòðàöèé èîíèçèðîâàííîãî Ñà, õîòÿ ìîëåêóëÿðíûå ìåõàíèçìû ýòîãî ñîáûòèÿ íå óñòàíîâëåíû.

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Hsu CY, Chertow GM. Elevations of serum phosphorus and potassium in mild to moderate chronic renal insufficiency. Nephrology Dialysis Transplantation. 2002;17(8):1419–1425
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    ÕÁÏ ïîâûøåíèå ÐÒÍ îïåðåæàåò ðàçâèòèå çíà÷èìûõ íàðóøåíèé êîíöåíòðàöèè Ñà è Ð â öèðêóëÿöèè, à äîëÿ áîëüíûõ ñ ïîâûøåíèåì ÐÒÍ ñóùåñòâåííî ïðåâûøàåò äîëè áîëüíûõ ñ ãèïîêàëüöèåìèé è ãèïåðôîñôàòåìèåé [9]. Êðîìå òîãî, óáåäèòåëüíî ïîêàçàíî, ÷òî êîíöåíòðàöèÿ Ð â öèðêóëÿöèè îñòàåòñÿ ó áîëüøèíñòâà áîëüíûõ â íîðìàëüíûõ ïðåäåëàõ, âïëîòü äî ñóùåñòâåííîãî ñíèæåíèÿ ÑÊÔ, ñîîòâåòñòâóþùåãî ÕÁÏ IV ñòàäèè
    Exact
    [9–11]
    Suffix
    . Ïî ìåðå ïðîãðåññèðîâàíèÿ ÕÁÏ ñûâîðîòî÷íàÿ êîíöåíòðàöèÿ è îáùåãî, è èîíèçèðîâàííîãî Ñà ïðè íàëè÷èè íåñóùåñòâåííûõ äåâèàöèé îñòàåòñÿ â íîðìàëüíûõ ïðåäåëàõ áåç ÿâíîãî ñíèæåíèÿ, âïëîòü äî ðàçâèòèÿ ÕÁÏ V ñòàäèè [9].

11
Levin A, Bakris GL, Molitch M et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney International 2007; 71 (1): 31–38
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    ÕÁÏ ïîâûøåíèå ÐÒÍ îïåðåæàåò ðàçâèòèå çíà÷èìûõ íàðóøåíèé êîíöåíòðàöèè Ñà è Ð â öèðêóëÿöèè, à äîëÿ áîëüíûõ ñ ïîâûøåíèåì ÐÒÍ ñóùåñòâåííî ïðåâûøàåò äîëè áîëüíûõ ñ ãèïîêàëüöèåìèé è ãèïåðôîñôàòåìèåé [9]. Êðîìå òîãî, óáåäèòåëüíî ïîêàçàíî, ÷òî êîíöåíòðàöèÿ Ð â öèðêóëÿöèè îñòàåòñÿ ó áîëüøèíñòâà áîëüíûõ â íîðìàëüíûõ ïðåäåëàõ, âïëîòü äî ñóùåñòâåííîãî ñíèæåíèÿ ÑÊÔ, ñîîòâåòñòâóþùåãî ÕÁÏ IV ñòàäèè
    Exact
    [9–11]
    Suffix
    . Ïî ìåðå ïðîãðåññèðîâàíèÿ ÕÁÏ ñûâîðîòî÷íàÿ êîíöåíòðàöèÿ è îáùåãî, è èîíèçèðîâàííîãî Ñà ïðè íàëè÷èè íåñóùåñòâåííûõ äåâèàöèé îñòàåòñÿ â íîðìàëüíûõ ïðåäåëàõ áåç ÿâíîãî ñíèæåíèÿ, âïëîòü äî ðàçâèòèÿ ÕÁÏ V ñòàäèè [9].

12
Murayama A, Takeyama K, Kitanaka S et al. Positive and negative regulations of the renal 25-hydroxyvitamin D3 1alpha-hydroxylase gene by parathyroid hormone, calcitonin, and 1alpha,25(OH)2D3 in intact animals. Endocrinology 1999;140(5):2224-2231
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    Ñíèæåíèå êàëüöèòðèîëà â öèðêóëÿöèè òàêæå òðóäíî áûëî áû îáúÿñíèòü â ñëó÷àÿõ óæå èìåþùåãîñÿ ïîâûøåíèÿ ÐÒÍ, òàê êàê ïîñëåäíèé, íàïðîòèâ, óâåëè÷èâàåò îáðàçîâàíèå êàëüöèòðèîëà â ðåçóëüòàòå ïîâûøåíèÿ àêòèâíîñòè 25(OH)D3 -1α-ãèäðîêñèëàçû
    Exact
    [12]
    Suffix
    . Òàêèì îáðàçîì, â ðàìêàõ «êëàññè÷åñêèõ» ïðåäñòàâëåíèé áûëî íåëüçÿ ïîëíîñòüþ îáúÿñíèòü ïîâûøåíèå ÐÒÍ ïðè ÕÁÏ, à ïîÿâëåíèå íîâûõ äàííûõ î ðåãóëÿöèè ãîìåîñòàçà Ð ïîçâîëÿåò â íàñòîÿùåå âðåìÿ ðàññìàòðèâàòü ïàòîãåíåç ÂÃÏÒ ñ èíûõ ïîçèöèé.

13
Shimada T, Mizutani S, Muto T et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci USA 2001; 98 (11): 6500– 6505
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  1. In-text reference with the coordinate start=8134
    Prefix
    Íîâûå ïàðàäèãìû, ñóùåñòâåííî èçìåíèâøèå ñîâðåìåííûå ïðåäñòàâëåíèÿ î ïàòîãåíåçå ÂÃÏÒ, â ïåðâóþ î÷åðåäü, áûëè ñâÿçàíû ñ îòêðûòèåì íîâûõ ôîñôàò-ðåãóëèðóþùèõ ôàêòîðîâ – ôàêòîðà ðîñòà ôèáðîáëàñòîâ 23 (FGF23) è áåëêà Klotho. FGF23 ïðåäñòàâëÿåò ñîáîé 32-kDa ïåïòèä, ñåêðåòèðóåìûé â öèðêóëÿöèþ îñòåîöèòàìè, îñòåîáëàñòàìè è îñòåîêëàñòàìè â îòâåò íà äåéñòâèå ãèïåðôîñôàòåìèè è êàëüöèòðèîëà
    Exact
    [13]
    Suffix
    . Êàê è ÏÒÃ, FGF23 îáëàäàåò ôîñôàòóðè÷åñêèì ýôôåêòîì è âûçûâàåò ñíèæåíèå Ð ñûâîðîòêè. FGF23 ðåàëèçóåò ñâîè ýôôåêòû, ñâÿçûâàÿñü ñî ñëîæíûì ðåöåïòîðîì, ñîñòîÿùèì èç ñîáñòâåííî FGF-ðåöåïòîðà [FGFR1, FGFR3 è(èëè) FGFR4] è êî-ðåöåïòîðà Klotho.

14
Kurosu H, Ogawa Y, Miyoshi M et al. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 2006 10;281(10):6120-6123
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  1. In-text reference with the coordinate start=8621
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    FGF23 ðåàëèçóåò ñâîè ýôôåêòû, ñâÿçûâàÿñü ñî ñëîæíûì ðåöåïòîðîì, ñîñòîÿùèì èç ñîáñòâåííî FGF-ðåöåïòîðà [FGFR1, FGFR3 è(èëè) FGFR4] è êî-ðåöåïòîðà Klotho. Klotho – 130-kDa òðàíñìåìáðàííûé ïðîòåèí, ïðåäñòàâëÿåò ñîáîé β-ãëþêîçèäàçó, êîòîðàÿ ñâÿçûâàåòñÿ ñ FGFR è Ñ-òåðìèíàëîì FGF23, ïðèâîäÿ ê êîíâåðòàöèè êàíîíè÷åñêèå FGFR â âûñîêîàôôèííûå ñïåöèôè÷åñêèå
    Exact
    [14]
    Suffix
    . Ñâîå íàçâàíèå îí ïîëó÷èë â ÷åñòü îäíîé èç òðåõ äðåâíåãðå÷åñêèõ áîãèíü ñóäüáû, êîòîðàÿ ïðÿäåò íèòü æèçíè, áëàãîäàðÿ ñâîåé ôåíîòèïè÷åñêîé ñâÿçè ñ ïðîöåññàìè ñòàðåíèÿ è ðåçêèì óêîðî÷åíèåì âðåìåíè æèçíè ó íîêàóòíûõ ïî Klotho æèâîòíûõ íà ôîíå ðàçâèòèÿ ãèïåðôîñôàòåìèè, ãèïåðêàëüöèåìèè, íåñìîòðÿ íà âûñîêîå ñîäåðæàíèå êàëüöèòðèîëà [15].

15
Kuro-o M, Matsumura Y, Aizawa H et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997; 390(6655): 45–51
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  1. In-text reference with the coordinate start=8947
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    Ñâîå íàçâàíèå îí ïîëó÷èë â ÷åñòü îäíîé èç òðåõ äðåâíåãðå÷åñêèõ áîãèíü ñóäüáû, êîòîðàÿ ïðÿäåò íèòü æèçíè, áëàãîäàðÿ ñâîåé ôåíîòèïè÷åñêîé ñâÿçè ñ ïðîöåññàìè ñòàðåíèÿ è ðåçêèì óêîðî÷åíèåì âðåìåíè æèçíè ó íîêàóòíûõ ïî Klotho æèâîòíûõ íà ôîíå ðàçâèòèÿ ãèïåðôîñôàòåìèè, ãèïåðêàëüöèåìèè, íåñìîòðÿ íà âûñîêîå ñîäåðæàíèå êàëüöèòðèîëà
    Exact
    [15]
    Suffix
    . Klotho, êàê êî-ðåöåïòîð FGF23, êðèòè÷åí äëÿ ðåàëèçàöèè áèîëîãè÷åñêîãî äåéñòâèÿ FGF23, íî òàêæå îáëàäàåò ðÿäîì ñîáñòâåííûõ ýôôåêòîâ, íåçàâèñèìûõ îò FGF23 (ñì.íèæå]. FGFR è Klotho ýêñïðåññèðóåòñÿ, ãëàâíûì îáðàçîì, â ïî÷êàõ è ÏÙÆ – äâóõ íàèáîëåå âàæíûõ îðãàíàõ, ó÷àñòâóþùèõ â ðåãóëÿöèè Ñà-Ð-îáìåíà.

16
Liu S, Vierthaler L, Tang W et al. FGFR3 and FGFR4 do not mediate renal effects of FGF23. J Am Soc Nephrol 2008; 19 (12): 2342–2350
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  1. In-text reference with the coordinate start=9690
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    Äåòàëè êîîïåðàòèâíîãî âçàèìîäåéñòâèÿ FGF23, FGFR è Klotho â èíãèáèðîâàíèè ðåàáñîðáöèè Ð îñòàþòñÿ ïðåäìåòîì äèñêóññèé, ïîñêîëüêó è Klotho, è FGFR1 ýêñïðåññèðóåòñÿ â îñíîâíîì â äèñòàëüíîì êàíàëüöå è ìåíüøå – â ïðîêñèìàëüíîì
    Exact
    [16]
    Suffix
    . Â òî æå âðåìÿ, îñíîâíûì ìåñòîì ðåàáñîðáöèè Ð ÿâëÿþòñÿ ïðîêñèìàëüíûå êàíàëüöû, êîòîðûå ýêñïðåññèðóþò òîëüêî FGFR3, íî íå FGFR1, FGFR2 èëè FGFR4. Îäíèì èç âîçìîæíûõ îáúÿñíåíèé ìîæåò áûòü ïàðàêðèííûé/àóòîêðèííûé ýôôåêò ýêñòðàöåëëþëÿðíîãî äîìåíà Klotho.

17
Hu MC, Shi M, Zhang J et al. Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J 2010; 24 (9): 3438–3450
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  1. In-text reference with the coordinate start=10144
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    Îäíèì èç âîçìîæíûõ îáúÿñíåíèé ìîæåò áûòü ïàðàêðèííûé/àóòîêðèííûé ýôôåêò ýêñòðàöåëëþëÿðíîãî äîìåíà Klotho. Ïîñëåäíèé ñïîñîáåí îòäåëÿòüñÿ è ïîïàäàòü â öèðêóëÿöèþ ïîä äåéñòâèåì ìåòàëëîïðîòåèíàç, âîçìîæíî, ñâÿçûâàÿñü ñ FGFR3 â ïðîêñèìàëüíîì êàíàëüöå è ïðîÿâëÿÿ ôîñôàòóðè÷åñêèé è äðóãèå àóòîêðèííûå ýôôåêòû
    Exact
    [17]
    Suffix
    . Äðóãîé êëþ÷åâîé àñïåêò áèîëîãè÷åñêîãî äåéñòâèÿ FGF23 çàêëþ÷àåòñÿ â ñíèæåíèè 1α-ãèäðîêñèëàçíîé àêòèâíîñòè (ïðîòèâîïîëîæíî ýôôåêòó PTH) è óâåëè÷åíèè àêòèâíîñòè 24-ãèäðîêñèëàçû â òóáóëÿðíîì ýïèòåëèè.

18
Saito H, Kusano K, Kinosaki M et al. Human fibroblast growth factor-23 mutants suppress Na+-dependent phosphate co-transport activity and 1alpha,25-dihydroxyvitamin D3 production. J Biol Chem 2003; 278 (4): 2206–2211
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    Äðóãîé êëþ÷åâîé àñïåêò áèîëîãè÷åñêîãî äåéñòâèÿ FGF23 çàêëþ÷àåòñÿ â ñíèæåíèè 1α-ãèäðîêñèëàçíîé àêòèâíîñòè (ïðîòèâîïîëîæíî ýôôåêòó PTH) è óâåëè÷åíèè àêòèâíîñòè 24-ãèäðîêñèëàçû â òóáóëÿðíîì ýïèòåëèè. Òàêèì îáðàçîì, FGF23 òîðìîçèò ñèíòåç 1,25(OH)2D è ÿâëÿåòñÿ åãî êîíòððåãóëÿòîðíûì ôàêòîðîì.  ðåçóëüòàòå ñíèæåíèÿ êàëüöèòðèîëà óìåíüøàþòñÿ êèøå÷íàÿ ýêñïðåññèÿ NPT2b è àáñîðáöèÿ Ð
    Exact
    [18, 19]
    Suffix
    . FGF23/Klotho òàêæå ó÷àñòâóþò â ðåãóëÿöèè PTH, äåéñòâóÿ ÷åðåç îïèñàííûå âûøå ðåöåïòîðû â ÏÙÆ. FGF23 ñíèæàåò ýêñïðåññèþ ìÐÍÊ PTH è åãî ñåêðåöèþ ÷åðåç ñòèìóëÿöèþ ñèñòåìû Klotho/ FGFR â ÏÙÆ. Åñòü ïðåäïîëîæåíèÿ î òîì, ÷òî, âëèÿÿ íà ëîêàëüíóþ 1α-ãèäðîêñèëàçíóþ àêòèâíîñòü â ÏÙÆ, FGF23 ìîæåò îêàçûâàòü âëèÿíèå íà ãåí ÐÒÍ ÷åðåç óâåëè÷åíèå ëîêàëüíîãî îáðàçîâàíèÿ êàëüöèòðèîëà.

19
Shimada T, Hasegawa H, Yamazaki Y et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004; 19(3): 429-435
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  1. In-text reference with the coordinate start=10524
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    Äðóãîé êëþ÷åâîé àñïåêò áèîëîãè÷åñêîãî äåéñòâèÿ FGF23 çàêëþ÷àåòñÿ â ñíèæåíèè 1α-ãèäðîêñèëàçíîé àêòèâíîñòè (ïðîòèâîïîëîæíî ýôôåêòó PTH) è óâåëè÷åíèè àêòèâíîñòè 24-ãèäðîêñèëàçû â òóáóëÿðíîì ýïèòåëèè. Òàêèì îáðàçîì, FGF23 òîðìîçèò ñèíòåç 1,25(OH)2D è ÿâëÿåòñÿ åãî êîíòððåãóëÿòîðíûì ôàêòîðîì.  ðåçóëüòàòå ñíèæåíèÿ êàëüöèòðèîëà óìåíüøàþòñÿ êèøå÷íàÿ ýêñïðåññèÿ NPT2b è àáñîðáöèÿ Ð
    Exact
    [18, 19]
    Suffix
    . FGF23/Klotho òàêæå ó÷àñòâóþò â ðåãóëÿöèè PTH, äåéñòâóÿ ÷åðåç îïèñàííûå âûøå ðåöåïòîðû â ÏÙÆ. FGF23 ñíèæàåò ýêñïðåññèþ ìÐÍÊ PTH è åãî ñåêðåöèþ ÷åðåç ñòèìóëÿöèþ ñèñòåìû Klotho/ FGFR â ÏÙÆ. Åñòü ïðåäïîëîæåíèÿ î òîì, ÷òî, âëèÿÿ íà ëîêàëüíóþ 1α-ãèäðîêñèëàçíóþ àêòèâíîñòü â ÏÙÆ, FGF23 ìîæåò îêàçûâàòü âëèÿíèå íà ãåí ÐÒÍ ÷åðåç óâåëè÷åíèå ëîêàëüíîãî îáðàçîâàíèÿ êàëüöèòðèîëà.

20
Аntoniucci DM, Yamashita T, Portale AA: Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men. J Clin Endocrinol Metab 2006; 91 (8): 3144–3149
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    Ïðè áîëüøîì ïîòðåáëåíèè Ð ñ ïèùåé âûñîêèé óðîâåíü FGF23 âûçûâàåò ôîñôàòóðèþ è èíãèáèðóåò ñèíòåç êàëüöèòðèîëà, ÷òî ïðèâîäèò ê ñíèæåíèþ êèøå÷íîé àáñîðáöèè Ð. Íàîáîðîò, ïðè îãðàíè÷åíèè ïîñòóïëåíèÿ Ð ñíèæåíèå óðîâíÿ FGF23 ïðèâîäèò ê ïîâûøåíèþ ðåàáñîðáöèè ôîñôàòîâ â ïî÷êå è óâåëè÷åíèþ âñàñûâàíèÿ Ð â êèøêå, â ðåçóëüòàòå óâåëè÷åíèÿ ñèíòåçà 1,25(OH)2D3
    Exact
    [20, 21]
    Suffix
    . Íåäàâíî òàêæå óñòàíîâëåíî, ÷òî ÐÒÍ òàêæå íåîáõîäèì è äëÿ îáðàçîâàíèÿ FGF23, è äëÿ ðåàëèçàöèè åãî ïî÷å÷íûõ ýôôåêòîâ, â òîì ÷èñëå è çà ñ÷åò ñòèìóëÿöèè ýêñïðåññèè Klotho [22]. Ýêñïðåññèÿ ãåíà Klotho òàêæå èíäóöèðóåòñÿ êàëüöèòðèîëîì [23].

21
Burnett SM, Gunawardene SC, Bringhurst FR et al. Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women. J Bone Miner Res 2006; 21 (8): 1187–1196
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    Ïðè áîëüøîì ïîòðåáëåíèè Ð ñ ïèùåé âûñîêèé óðîâåíü FGF23 âûçûâàåò ôîñôàòóðèþ è èíãèáèðóåò ñèíòåç êàëüöèòðèîëà, ÷òî ïðèâîäèò ê ñíèæåíèþ êèøå÷íîé àáñîðáöèè Ð. Íàîáîðîò, ïðè îãðàíè÷åíèè ïîñòóïëåíèÿ Ð ñíèæåíèå óðîâíÿ FGF23 ïðèâîäèò ê ïîâûøåíèþ ðåàáñîðáöèè ôîñôàòîâ â ïî÷êå è óâåëè÷åíèþ âñàñûâàíèÿ Ð â êèøêå, â ðåçóëüòàòå óâåëè÷åíèÿ ñèíòåçà 1,25(OH)2D3
    Exact
    [20, 21]
    Suffix
    . Íåäàâíî òàêæå óñòàíîâëåíî, ÷òî ÐÒÍ òàêæå íåîáõîäèì è äëÿ îáðàçîâàíèÿ FGF23, è äëÿ ðåàëèçàöèè åãî ïî÷å÷íûõ ýôôåêòîâ, â òîì ÷èñëå è çà ñ÷åò ñòèìóëÿöèè ýêñïðåññèè Klotho [22]. Ýêñïðåññèÿ ãåíà Klotho òàêæå èíäóöèðóåòñÿ êàëüöèòðèîëîì [23].

22
Lуpez I, Rodrнguez-Ortiz ME, Almadйn Y et al. Direct and indirect effects of parathyroid hormone on circulating levels of fibroblast growth factor 23 in vivo. Kidney Int 2011; 80 (5): 475–482
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    Íàîáîðîò, ïðè îãðàíè÷åíèè ïîñòóïëåíèÿ Ð ñíèæåíèå óðîâíÿ FGF23 ïðèâîäèò ê ïîâûøåíèþ ðåàáñîðáöèè ôîñôàòîâ â ïî÷êå è óâåëè÷åíèþ âñàñûâàíèÿ Ð â êèøêå, â ðåçóëüòàòå óâåëè÷åíèÿ ñèíòåçà 1,25(OH)2D3 [20, 21]. Íåäàâíî òàêæå óñòàíîâëåíî, ÷òî ÐÒÍ òàêæå íåîáõîäèì è äëÿ îáðàçîâàíèÿ FGF23, è äëÿ ðåàëèçàöèè åãî ïî÷å÷íûõ ýôôåêòîâ, â òîì ÷èñëå è çà ñ÷åò ñòèìóëÿöèè ýêñïðåññèè Klotho
    Exact
    [22]
    Suffix
    . Ýêñïðåññèÿ ãåíà Klotho òàêæå èíäóöèðóåòñÿ êàëüöèòðèîëîì [23].  öåëîì, â íàñòîÿùåå âðåìÿ î÷åâèäíî, ÷òî ñóùåñòâóåò áîëåå ñëîæíàÿ, ÷åì ïðåäïîëàãàëîñü ðàíåå, ñèñòåìà êîíòðîëÿ ìèíåðàëüíîãî îáìåíà è, â ÷àñòíîñòè, ïóëà ôîñôàòîâ.

23
Tsujikawa H, Kurotaki Y, Fujimori T et al. Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. Mol Endocrinol 2003; 17 (12): 2393–2403
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    Íåäàâíî òàêæå óñòàíîâëåíî, ÷òî ÐÒÍ òàêæå íåîáõîäèì è äëÿ îáðàçîâàíèÿ FGF23, è äëÿ ðåàëèçàöèè åãî ïî÷å÷íûõ ýôôåêòîâ, â òîì ÷èñëå è çà ñ÷åò ñòèìóëÿöèè ýêñïðåññèè Klotho [22]. Ýêñïðåññèÿ ãåíà Klotho òàêæå èíäóöèðóåòñÿ êàëüöèòðèîëîì
    Exact
    [23]
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    .  öåëîì, â íàñòîÿùåå âðåìÿ î÷åâèäíî, ÷òî ñóùåñòâóåò áîëåå ñëîæíàÿ, ÷åì ïðåäïîëàãàëîñü ðàíåå, ñèñòåìà êîíòðîëÿ ìèíåðàëüíîãî îáìåíà è, â ÷àñòíîñòè, ïóëà ôîñôàòîâ. Ýòà ñèñòåìà ñîñòîèò èç ìåõàíèçìîâ âçàèìîäåéñòâèÿ, ïî êðàéíåé ìåðå, òðåõ òåñíî âçàèìîñâÿçàííûõ ìåæäó ñîáîé ñóáñèñòåì – ÐÒÍ, FGF23/Klotho è êàëüöèòðèîëà (ðèñ.1).

24
Isakova T, Wahl P, Vargas GS et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int 2011; 79 (12): 1370-1378
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  1. In-text reference with the coordinate start=12530
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     íàñòîÿùåå âðåìÿ óñòàíîâëåíî, ÷òî ïîâûøåíèå FGF23 â öèðêóëÿöèè ïðîèñõîäèò óæå íà ðàííèõ ñòàäèÿõ ÕÁÏ ïðè íåáîëüøîì ñíèæåíèè ÑÊÔ. Íà áîëåå ïîçäíèõ ñòàäèÿõ ÕÁÏ ïðîäóêöèÿ FGF23 åùå áîëüøå óâåëè÷èâàåòñÿ, äîñòèãàÿ ìàêñèìàëüíûõ çíà÷åíèé ïðè ÕÁÏ V ñòàäèè è ïðåâûøàÿ íîðìàëüíûé óðîâåíü â äåñÿòêè/ñîòíè (!) ðàç
    Exact
    [24]
    Suffix
    .  ýêñïåðèìåíòàëüíûõ è êëèíè÷åñêèõ èññëåäîâàíèÿõ ïðîäåìîíñòðèðîâàíî, ÷òî óâåëè÷åíèå FGF23 è ÐÒÍ ïðîèñõîäèò ïî÷òè Рис. 1. Схема взаимодействия трех основных систем контроля баланса фосфатов, построенная на механизмах обратной связи (плюсами отмечены активирующие влияния, минусами – ингибирующие). ïàðàëëåëüíî ñ óâåëè÷åíèåì ýêñêðåòèðóåìîé ôðàêöèè ôîñôàòîâ â ìî÷å, ïðîòèâîäåéñòâóÿ

  2. In-text reference with the coordinate start=13142
    Prefix
    систем контроля баланса фосфатов, построенная на механизмах обратной связи (плюсами отмечены активирующие влияния, минусами – ингибирующие). ïàðàëëåëüíî ñ óâåëè÷åíèåì ýêñêðåòèðóåìîé ôðàêöèè ôîñôàòîâ â ìî÷å, ïðîòèâîäåéñòâóÿ èõ ðåòåíöèè [25–28]. Âìåñòå ñ òåì, ðîñò êîíöåíòðàöèè FGF23 ÿâëÿåòñÿ ïåðâè÷íûì ñîáûòèåì ïî îòíîøåíèþ ê ÐÒÍ, ïîñêîëüêó ñóùåñòâåííî îïåðåæàåò ïîâûøåíèå ïîñëåäíåãî
    Exact
    [24]
    Suffix
    . Î÷åâèäíî, ÷òî ïðîäóêöèþ ýòîãî ãîðìîíà ñòèìóëèðóåò íå ñàìà ãèïåðôîñôàòåìèÿ, ïîñêîëüêó â òî âðåìÿ, êîãäà FGF23 óæå ñóùåñòâåííî ïîâûøåí íà I–II ñòàäèÿõ ÕÁÏ, óðîâåíü Ð ó áîëüíûõ îñòàåòñÿ íîðìàëüíûì äî ñíèæåíèÿ ÑÊÔ 30–35 ìë/ìèí.

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    Ñòðóêòóðíàÿ ïåðåñòðîéêà è ðåöåïòîðíûé àïïàðàò ÏÙÆ ïðè ÂÃÏÒ. Îäèí èç âàæíûõ äëÿ ïîíèìàíèÿ ìåõàíèçìîâ ðàçâèòèÿ ÂÃÏÒ âîïðîñîâ çàêëþ÷àåòñÿ â òîì, ïî÷åìó, íåñìîòðÿ íà ïîâûøåíèå FGF23 íà ðàííèõ ñòàäèÿõ ôîðìèðîâàíèÿ ÂÃÏÒ, ïðîèñõîäèò è óâåëè÷åíèå ñåêðåöèè ÐÒÍ
    Exact
    [24]
    Suffix
    . Ãèïåðïðîäóêöèÿ FGF23, âûçûâàÿ ôîñôàòóðèþ, äîëæíà áûëà áû ñîïðîâîæäàòüñÿ ïîñëåäóþùåé äåïðåññèåé ñèíòåçà ÐÒÍ â ðåçóëüòàòå âçàèìîäåéñòâèÿ FGF23 ñ FGFR/Klotho â ÏÙÆ, àêòèâàöèÿ êîòîðûõ ñíèæàåò ýêñïðåññèþ ìÐÍÊ PTH è åãî ñåêðåöèþ (ñì. ðèñ. 2).

25
Gutierrez O, Isakova T, Rhee E et al. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. Journal of the American Society of Nephrology 2005; 16 (7):2205–2215
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  1. In-text reference with the coordinate start=12993
    Prefix
    Схема взаимодействия трех основных систем контроля баланса фосфатов, построенная на механизмах обратной связи (плюсами отмечены активирующие влияния, минусами – ингибирующие). ïàðàëëåëüíî ñ óâåëè÷åíèåì ýêñêðåòèðóåìîé ôðàêöèè ôîñôàòîâ â ìî÷å, ïðîòèâîäåéñòâóÿ èõ ðåòåíöèè
    Exact
    [25–28]
    Suffix
    . Âìåñòå ñ òåì, ðîñò êîíöåíòðàöèè FGF23 ÿâëÿåòñÿ ïåðâè÷íûì ñîáûòèåì ïî îòíîøåíèþ ê ÐÒÍ, ïîñêîëüêó ñóùåñòâåííî îïåðåæàåò ïîâûøåíèå ïîñëåäíåãî [24]. Î÷åâèäíî, ÷òî ïðîäóêöèþ ýòîãî ãîðìîíà ñòèìóëèðóåò íå ñàìà ãèïåðôîñôàòåìèÿ, ïîñêîëüêó â òî âðåìÿ, êîãäà FGF23 óæå ñóùåñòâåííî ïîâûøåí íà I–II ñòàäèÿõ ÕÁÏ, óðîâåíü Ð ó áîëüíûõ îñòàåòñÿ íîðìàëüíûì äî ñíèæåíèÿ ÑÊÔ 30–35 ìë/ìèí.

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    Prefix
    Ñ îäíîé ñòîðîíû, óâåëè÷åíèå ïðîäóêöèè FGF23, íà÷èíàÿ ñ ðàííèõ ñòàäèé ÕÁÏ, ïðåïÿòñòâóåò ðàçâèòèþ ãèïåðôîñôàòåìèè è îáúÿñíÿåò, ïî÷åìó ñûâîðîòî÷íàÿ êîíöåíòðàöèÿ Ð îñòàåòñÿ íîðìàëüíîé, âïëîòü äî âûðàæåííîãî ñíèæåíèÿ ÑÊÔ. Ñ äðóãîé ñòîðîíû – FGF23 ïðèâîäèò ê èíãèáèðîâàíèþ îáðàçîâàíèÿ êàëüöèòðèîëà è ôîðìèðîâàíèþ ÂÃÏÒ çà ñ÷åò îñëàáëåíèÿ ãåíîìíûõ ìåõàíèçìîâ êîíòðîëÿ ñèíòåçà ÐÒÍ
    Exact
    [25–28]
    Suffix
    (ñì. ðèñ. 2). Âàæíûé äëÿ ïîíèìàíèÿ ïàòîãåíåçà ÂÃÏÒ, íî ïîêà îòêðûòûé âîïðîñ, çàêëþ÷àåòñÿ â òîì, íàñêîëüêî áûñòðî ðåàãèðóåò ñèñòåìà PTH/FGF23 íà èçìåíåíèå áàëàíñà ôîñôàòîâ â ðåçóëüòàòå ïèùåâîé íàãðóçêè/ñíèæåíèÿ ÑÊÔ.

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Liu S, Quarles LD. How fibroblast growth factor 23 works. Journal of the American Society of Nephrology 2007;18 (6):1637–1647
Total in-text references: 2
  1. In-text reference with the coordinate start=12993
    Prefix
    Схема взаимодействия трех основных систем контроля баланса фосфатов, построенная на механизмах обратной связи (плюсами отмечены активирующие влияния, минусами – ингибирующие). ïàðàëëåëüíî ñ óâåëè÷åíèåì ýêñêðåòèðóåìîé ôðàêöèè ôîñôàòîâ â ìî÷å, ïðîòèâîäåéñòâóÿ èõ ðåòåíöèè
    Exact
    [25–28]
    Suffix
    . Âìåñòå ñ òåì, ðîñò êîíöåíòðàöèè FGF23 ÿâëÿåòñÿ ïåðâè÷íûì ñîáûòèåì ïî îòíîøåíèþ ê ÐÒÍ, ïîñêîëüêó ñóùåñòâåííî îïåðåæàåò ïîâûøåíèå ïîñëåäíåãî [24]. Î÷åâèäíî, ÷òî ïðîäóêöèþ ýòîãî ãîðìîíà ñòèìóëèðóåò íå ñàìà ãèïåðôîñôàòåìèÿ, ïîñêîëüêó â òî âðåìÿ, êîãäà FGF23 óæå ñóùåñòâåííî ïîâûøåí íà I–II ñòàäèÿõ ÕÁÏ, óðîâåíü Ð ó áîëüíûõ îñòàåòñÿ íîðìàëüíûì äî ñíèæåíèÿ ÑÊÔ 30–35 ìë/ìèí.

  2. In-text reference with the coordinate start=17290
    Prefix
    Ñ îäíîé ñòîðîíû, óâåëè÷åíèå ïðîäóêöèè FGF23, íà÷èíàÿ ñ ðàííèõ ñòàäèé ÕÁÏ, ïðåïÿòñòâóåò ðàçâèòèþ ãèïåðôîñôàòåìèè è îáúÿñíÿåò, ïî÷åìó ñûâîðîòî÷íàÿ êîíöåíòðàöèÿ Ð îñòàåòñÿ íîðìàëüíîé, âïëîòü äî âûðàæåííîãî ñíèæåíèÿ ÑÊÔ. Ñ äðóãîé ñòîðîíû – FGF23 ïðèâîäèò ê èíãèáèðîâàíèþ îáðàçîâàíèÿ êàëüöèòðèîëà è ôîðìèðîâàíèþ ÂÃÏÒ çà ñ÷åò îñëàáëåíèÿ ãåíîìíûõ ìåõàíèçìîâ êîíòðîëÿ ñèíòåçà ÐÒÍ
    Exact
    [25–28]
    Suffix
    (ñì. ðèñ. 2). Âàæíûé äëÿ ïîíèìàíèÿ ïàòîãåíåçà ÂÃÏÒ, íî ïîêà îòêðûòûé âîïðîñ, çàêëþ÷àåòñÿ â òîì, íàñêîëüêî áûñòðî ðåàãèðóåò ñèñòåìà PTH/FGF23 íà èçìåíåíèå áàëàíñà ôîñôàòîâ â ðåçóëüòàòå ïèùåâîé íàãðóçêè/ñíèæåíèÿ ÑÊÔ.

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Priе D, Torres PU, Friedlander G. Latest findings in phosphate homeostasis. Kidney International 2009; 75 (9): 882– 889
Total in-text references: 2
  1. In-text reference with the coordinate start=12993
    Prefix
    Схема взаимодействия трех основных систем контроля баланса фосфатов, построенная на механизмах обратной связи (плюсами отмечены активирующие влияния, минусами – ингибирующие). ïàðàëëåëüíî ñ óâåëè÷åíèåì ýêñêðåòèðóåìîé ôðàêöèè ôîñôàòîâ â ìî÷å, ïðîòèâîäåéñòâóÿ èõ ðåòåíöèè
    Exact
    [25–28]
    Suffix
    . Âìåñòå ñ òåì, ðîñò êîíöåíòðàöèè FGF23 ÿâëÿåòñÿ ïåðâè÷íûì ñîáûòèåì ïî îòíîøåíèþ ê ÐÒÍ, ïîñêîëüêó ñóùåñòâåííî îïåðåæàåò ïîâûøåíèå ïîñëåäíåãî [24]. Î÷åâèäíî, ÷òî ïðîäóêöèþ ýòîãî ãîðìîíà ñòèìóëèðóåò íå ñàìà ãèïåðôîñôàòåìèÿ, ïîñêîëüêó â òî âðåìÿ, êîãäà FGF23 óæå ñóùåñòâåííî ïîâûøåí íà I–II ñòàäèÿõ ÕÁÏ, óðîâåíü Ð ó áîëüíûõ îñòàåòñÿ íîðìàëüíûì äî ñíèæåíèÿ ÑÊÔ 30–35 ìë/ìèí.

  2. In-text reference with the coordinate start=17290
    Prefix
    Ñ îäíîé ñòîðîíû, óâåëè÷åíèå ïðîäóêöèè FGF23, íà÷èíàÿ ñ ðàííèõ ñòàäèé ÕÁÏ, ïðåïÿòñòâóåò ðàçâèòèþ ãèïåðôîñôàòåìèè è îáúÿñíÿåò, ïî÷åìó ñûâîðîòî÷íàÿ êîíöåíòðàöèÿ Ð îñòàåòñÿ íîðìàëüíîé, âïëîòü äî âûðàæåííîãî ñíèæåíèÿ ÑÊÔ. Ñ äðóãîé ñòîðîíû – FGF23 ïðèâîäèò ê èíãèáèðîâàíèþ îáðàçîâàíèÿ êàëüöèòðèîëà è ôîðìèðîâàíèþ ÂÃÏÒ çà ñ÷åò îñëàáëåíèÿ ãåíîìíûõ ìåõàíèçìîâ êîíòðîëÿ ñèíòåçà ÐÒÍ
    Exact
    [25–28]
    Suffix
    (ñì. ðèñ. 2). Âàæíûé äëÿ ïîíèìàíèÿ ïàòîãåíåçà ÂÃÏÒ, íî ïîêà îòêðûòûé âîïðîñ, çàêëþ÷àåòñÿ â òîì, íàñêîëüêî áûñòðî ðåàãèðóåò ñèñòåìà PTH/FGF23 íà èçìåíåíèå áàëàíñà ôîñôàòîâ â ðåçóëüòàòå ïèùåâîé íàãðóçêè/ñíèæåíèÿ ÑÊÔ.

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Wolf M. Forging forward with 10 burning questions on FGF23 in kidney disease. Journal of the American Society of Nephrology 2010; 21 (9): 1427–1435
Total in-text references: 2
  1. In-text reference with the coordinate start=12993
    Prefix
    Схема взаимодействия трех основных систем контроля баланса фосфатов, построенная на механизмах обратной связи (плюсами отмечены активирующие влияния, минусами – ингибирующие). ïàðàëëåëüíî ñ óâåëè÷åíèåì ýêñêðåòèðóåìîé ôðàêöèè ôîñôàòîâ â ìî÷å, ïðîòèâîäåéñòâóÿ èõ ðåòåíöèè
    Exact
    [25–28]
    Suffix
    . Âìåñòå ñ òåì, ðîñò êîíöåíòðàöèè FGF23 ÿâëÿåòñÿ ïåðâè÷íûì ñîáûòèåì ïî îòíîøåíèþ ê ÐÒÍ, ïîñêîëüêó ñóùåñòâåííî îïåðåæàåò ïîâûøåíèå ïîñëåäíåãî [24]. Î÷åâèäíî, ÷òî ïðîäóêöèþ ýòîãî ãîðìîíà ñòèìóëèðóåò íå ñàìà ãèïåðôîñôàòåìèÿ, ïîñêîëüêó â òî âðåìÿ, êîãäà FGF23 óæå ñóùåñòâåííî ïîâûøåí íà I–II ñòàäèÿõ ÕÁÏ, óðîâåíü Ð ó áîëüíûõ îñòàåòñÿ íîðìàëüíûì äî ñíèæåíèÿ ÑÊÔ 30–35 ìë/ìèí.

  2. In-text reference with the coordinate start=17290
    Prefix
    Ñ îäíîé ñòîðîíû, óâåëè÷åíèå ïðîäóêöèè FGF23, íà÷èíàÿ ñ ðàííèõ ñòàäèé ÕÁÏ, ïðåïÿòñòâóåò ðàçâèòèþ ãèïåðôîñôàòåìèè è îáúÿñíÿåò, ïî÷åìó ñûâîðîòî÷íàÿ êîíöåíòðàöèÿ Ð îñòàåòñÿ íîðìàëüíîé, âïëîòü äî âûðàæåííîãî ñíèæåíèÿ ÑÊÔ. Ñ äðóãîé ñòîðîíû – FGF23 ïðèâîäèò ê èíãèáèðîâàíèþ îáðàçîâàíèÿ êàëüöèòðèîëà è ôîðìèðîâàíèþ ÂÃÏÒ çà ñ÷åò îñëàáëåíèÿ ãåíîìíûõ ìåõàíèçìîâ êîíòðîëÿ ñèíòåçà ÐÒÍ
    Exact
    [25–28]
    Suffix
    (ñì. ðèñ. 2). Âàæíûé äëÿ ïîíèìàíèÿ ïàòîãåíåçà ÂÃÏÒ, íî ïîêà îòêðûòûé âîïðîñ, çàêëþ÷àåòñÿ â òîì, íàñêîëüêî áûñòðî ðåàãèðóåò ñèñòåìà PTH/FGF23 íà èçìåíåíèå áàëàíñà ôîñôàòîâ â ðåçóëüòàòå ïèùåâîé íàãðóçêè/ñíèæåíèÿ ÑÊÔ.

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Berndt T, Kumar R. Novel mechanisms in the regulation of phosphorus homeostasis. Physiology 2009; 24 (1): 17–25
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    Ïîêà, îäíàêî, îñòàåòñÿ íåèçâåñòíûì, êàê îðãàíèçì «÷óâñòâóåò» èçìåíåíèÿ ïèùåâîé íàãðóçêè è áàëàíñ Ð è ÷òî ÿâëÿåòñÿ íåïîñðåäñòâåííûì ìåññåíäæåðîì, ïðèâîäÿùèì ê èíäóêöèè ñèíòåçà FGF23 â îñòåîöèòàõ. Èçáûòî÷íûé ñèíòåç FGF23 íà ðàííèõ ñòàäèÿõ ÕÁÏ ïðîèñõîäèò, ïðåäïîëîæèòåëüíî, âñëåäñòâèå ðåòåíöèè Ð è íà÷àëüíîãî (òðàíçèòîðíîãî) óâåëè÷åíèÿ âíåêëåòî÷íîãî ïóëà Ð/Ð â öèðêóëÿöèè
    Exact
    [29]
    Suffix
    . Ïðåäïîëîæèòåëüíî, ïåðåõîä îò íåéòðàëüíîãî ê ïîçèòèâíîìó áàëàíñó ôîñôàòîâ çàïóñêàåò íåêèé «ôîñôàòíûé ñåíñîð» â îñòåîöèòàõ, ïðèâîäÿ ê èçáûòî÷íîìó îáðàçîâàíèþ FGF23 (ðèñ. 2). Íåäàâíî, Ò. Berndt è ñîàâò. ïðîäåìîíñòðèðîâàëè, ÷òî ââåäåíèå Ð â äâåíàäöàòèïåðñòíóþ êèøêó (íî íå â äðóãèå îòäåëû ÆÊÒ) íîðìàëüíûõ êðûñ áûñòðî âûçûâàåò óâåëè÷åíèå åãî ïî÷å÷íîé ýêñêðåöèè, áåç èçìåíåíèÿ ôèëüòðàöèîííîé çàãðóçêè è F

  2. In-text reference with the coordinate start=16534
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    к семейству TRP (transient receptor potential); ROMK1 – калиевый канал наружной медуллы; PiT-1 – натрий-зависимый фосфатный траспортер. íå èçìåíÿåòñÿ ïðè äîñòèæåíèÿ ãèïåðôîñôàòåìèè íà ôîíå âíóòðèâåííîãî ââåäåíèÿ Ð [32]. Ïðèâåäåííûå äàííûå ïîçâîëÿþò ïðåäïîëàãàòü íàëè÷èå îòäåëüíîé ñèñòåìû ôîñôàòíûõ ñåíñîðîâ â êèøêå è/ èëè èíòåñòèíàëüíûõ ìîëåêóë ñ ôîñôîòîíè÷åñêèì äåéñòâèåì
    Exact
    [29]
    Suffix
    . Ðåçîííîñòü ïîäîáíûõ ïðåäïîëîæåíèé î íåèçâåñòíûõ ïîêà ìåõàíèçìàõ ðåöåïöèè ôîñôàòíîãî ïóëà òåîðåòè÷åñêè îïðàâäàíà è òåì, ÷òî âñå èçâåñòíûå ìîùíûå ðåãóëÿòîðû ìèíåðàëüíîãî îáìåíà èìåþò ñâîè «ïðåäñòàâèòåëüñòâà» â ÏÙÆ â âèäå ñîîòâåòñòâóþùèõ ðåöåïòîðíûõ ñèñòåì – FGFR/Klotho, VDR, CaSR.

30
Berndt T, Thomas LF, Craig TA et al. Evidence for a signaling axis by which intestinal phosphate rapidly modulates renal phosphate reabsorption. Proc Natl Acad Sci USA 2007; 104 (26): 11085–11090
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  1. In-text reference with the coordinate start=14329
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    è ñîàâò. ïðîäåìîíñòðèðîâàëè, ÷òî ââåäåíèå Ð â äâåíàäöàòèïåðñòíóþ êèøêó (íî íå â äðóãèå îòäåëû ÆÊÒ) íîðìàëüíûõ êðûñ áûñòðî âûçûâàåò óâåëè÷åíèå åãî ïî÷å÷íîé ýêñêðåöèè, áåç èçìåíåíèÿ ôèëüòðàöèîííîé çàãðóçêè è FGF-23, êàê â äåíåðâèðîâàííûõ ïî÷êàõ, òàê è ó æèâîòíûõ ñ óäàëåííûìè ÏÙÆ. Ãîìîãåíàòû äóîäåíàëüíîé ñëèçèñòîé ââîäèìûå âíóòðèâåííî, òàêæå ïðèâîäèëè ê áûñòðîìó óâåëè÷åíèþ ìî÷åâîé ýêñêðåöèè Ð
    Exact
    [30]
    Suffix
    . Èíòåðåñíî è òî, ÷òî ðåçêîå ñíèæåíèå èíòåñòèíàëüíîãî ñîäåðæàíèÿ Ð óæå â òå÷åíèå 2 ÷ ïðèâîäèò ê ñíèæåíèþ ÐÒÍ ïðè ýêñïåðèìåíòàëüíîì ÂÃÏÒ, õîòÿ îñòðîå ñíèæåíèå óðîâíÿ ôîñôàòåìèè òàêèì ýôôåêòîì íà ÏÙÆ íå îáëàäàåò [31].

31
Martin DR, Ritter CS, Slatopolsky E et al. Acute regulation of parathyroid hormone by dietary phosphate. Am J Physiol Endocrinol Metab 2005; 289 (4): E729–E734.
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  1. In-text reference with the coordinate start=14546
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    Èíòåðåñíî è òî, ÷òî ðåçêîå ñíèæåíèå èíòåñòèíàëüíîãî ñîäåðæàíèÿ Ð óæå â òå÷åíèå 2 ÷ ïðèâîäèò ê ñíèæåíèþ ÐÒÍ ïðè ýêñïåðèìåíòàëüíîì ÂÃÏÒ, õîòÿ îñòðîå ñíèæåíèå óðîâíÿ ôîñôàòåìèè òàêèì ýôôåêòîì íà ÏÙÆ íå îáëàäàåò
    Exact
    [31]
    Suffix
    . Êðîìå òîãî, èçâåñòíî, ÷òî óðîâåíü FGF23 Рис.2. Принципиальная схема взаимодействий фосфат-ругулирующих систем и их изменений при развитии и прогрессировании вторичного гиперпаратиреоза (комментарии в тексте).

32
Ito N, Fukumoto S, Takeuchi Y et al. Effect of acute changes of serum phosphate on fibroblast growth factor (FGF)23 levels in humans. J Bone Miner Metab 2007; 25 (6): 419–422
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  1. In-text reference with the coordinate start=16375
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    котранспортеры; э-Klotho – экстрацеллюлярный домен Klotho; TRPV5, TRPV6 – Ca2+- селективные ваниллоидные мембранные катионные каналы, относящиеся к семейству TRP (transient receptor potential); ROMK1 – калиевый канал наружной медуллы; PiT-1 – натрий-зависимый фосфатный траспортер. íå èçìåíÿåòñÿ ïðè äîñòèæåíèÿ ãèïåðôîñôàòåìèè íà ôîíå âíóòðèâåííîãî ââåäåíèÿ Ð
    Exact
    [32]
    Suffix
    . Ïðèâåäåííûå äàííûå ïîçâîëÿþò ïðåäïîëàãàòü íàëè÷èå îòäåëüíîé ñèñòåìû ôîñôàòíûõ ñåíñîðîâ â êèøêå è/ èëè èíòåñòèíàëüíûõ ìîëåêóë ñ ôîñôîòîíè÷åñêèì äåéñòâèåì [29]. Ðåçîííîñòü ïîäîáíûõ ïðåäïîëîæåíèé î íåèçâåñòíûõ ïîêà ìåõàíèçìàõ ðåöåïöèè ôîñôàòíîãî ïóëà òåîðåòè÷åñêè îïðàâäàíà è òåì, ÷òî âñå èçâåñòíûå ìîùíûå ðåãóëÿòîðû ìèíåðàëüíîãî îáìåíà èìåþò ñâîè «ïðåäñòàâèòåëüñòâà» â ÏÙÆ â âèäå ñîîòâåòñòâóþùèõ ðåöå

33
Isakova T, Gutierrez O, Shah A et al. Postprandial mineral metabolism and secondary hyperparathyroidism in early CKD. J Am Soc Nephrol 2008; 19 (3): 615-623
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  1. In-text reference with the coordinate start=17680
    Prefix
    Âàæíûé äëÿ ïîíèìàíèÿ ïàòîãåíåçà ÂÃÏÒ, íî ïîêà îòêðûòûé âîïðîñ, çàêëþ÷àåòñÿ â òîì, íàñêîëüêî áûñòðî ðåàãèðóåò ñèñòåìà PTH/FGF23 íà èçìåíåíèå áàëàíñà ôîñôàòîâ â ðåçóëüòàòå ïèùåâîé íàãðóçêè/ñíèæåíèÿ ÑÊÔ.  îäíîì èç íåäàâíèõ èññëåäîâàíèé, ïðîâåäåííûì ñðåäè áîëüíûõ ñ ÕÁÏ III–IV ñòàäèé è ÑÊÔ 20–45 ìë/ìèí è çäîðîâûõ ëèö, áûëè èçó÷åíû ýôôåêòû îñòðîé ïèùåâîé íàãðóçêè ôîñôàòàìè
    Exact
    [33]
    Suffix
    . Íè â îäíîé èç 2 ãðóïï ÷åðåç 4 ÷ ïîñëå ïðèåìà 500 ìã ôîñôàòîâ íå áûëî âûÿâëåíî ãèïåðôîñôàòåìèè.  òî æå âðåìÿ ó çäîðîâûõ îòìå÷åíî áûñòðîå è ñóùåñòâåííî óâåëè÷åíèå âûäåëåíèÿ Ð ñ ìî÷îé, íî ó áîëüíûõ ñ ÕÁÏ, èìåâøèõ èñõîäíî çíà÷èòåëüíî áîëåå âûñîêóþ ýêñêðåòèðóåìóþ ôðàêöèþ Ð, áûë îòìå÷åí òîëüêî íåäîñòîâåðíûé òðåíä ê åå äàëüíåéøåìó óâåëè÷åíèþ.

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     òî æå âðåìÿ ó çäîðîâûõ îòìå÷åíî áûñòðîå è ñóùåñòâåííî óâåëè÷åíèå âûäåëåíèÿ Ð ñ ìî÷îé, íî ó áîëüíûõ ñ ÕÁÏ, èìåâøèõ èñõîäíî çíà÷èòåëüíî áîëåå âûñîêóþ ýêñêðåòèðóåìóþ ôðàêöèþ Ð, áûë îòìå÷åí òîëüêî íåäîñòîâåðíûé òðåíä ê åå äàëüíåéøåìó óâåëè÷åíèþ. Ïðèðîñòà PTH è FGF23 ïðè ýòîì â îáåèõ ãðóïïàõ íå áûëî, õîòÿ èõ èñõîäíûé óðîâåíü áûë âûøå ó áîëüíûõ ñ ÕÁÏ
    Exact
    [33]
    Suffix
    . Ïðèâåäåííûå äàííûå ïîçâîëÿþò ïðåäïîëàãàòü, ÷òî FGF23 ñàì ïî ñåáå íå ÿâëÿåòñÿ îñòðîôàçîâûì ôîñôîòîíèíîì, à åãî äåéñòâèå âîçìîæíî ðåàëèçóåòñÿ íà ðåöåïòîðíîì óðîâíå çà ñ÷åò Klotho. Áîëåå âåðîÿòíî, ÷òî FGF23 äåéñòâóåò êàê ñòðàòåãè÷åñêèé ðåãóëÿòîð ñòîéêî-ïîçèòèâíîãî áàëàíñà Ð, êîòîðûé ñîïóòñòâóåò ïðîãðåññèðîâàíèþ ÕÁÏ.

34
Cha SK, Ortega B, Kurosu H et al. Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1. Proc Natl Acad Sci USA 2008; 105 (28): 9805–9810
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  1. In-text reference with the coordinate start=18613
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    Áîëåå âåðîÿòíî, ÷òî FGF23 äåéñòâóåò êàê ñòðàòåãè÷åñêèé ðåãóëÿòîð ñòîéêî-ïîçèòèâíîãî áàëàíñà Ð, êîòîðûé ñîïóòñòâóåò ïðîãðåññèðîâàíèþ ÕÁÏ. FGF23-íåçàâèñèìûå ýôôåêòû Klotho. Èçâåñòíî, ÷òî Klotho ìîæåò íåçàâèñèìî îò FGF23 ìîäóëèðîâàòü ñåêðåöèþ PTH: êîñâåííî – ÷åðåç òóáóëÿðíóþ ðåàáñîðáöèþ Ñà è CaSR
    Exact
    [34]
    Suffix
    è ïðÿìî – ÷åðåç âîçäåéñòâèå íà Na+/K+-ATP-àçíóþ àêòèâíîñòü â ÏÙÆ [35]. Ïîñëåäíèé ìåõàíèçì, â îòëè÷èå îò ïðÿìîãî ýôôåêòà FGF23 íà ÏÙÆ, ïðèâîäèò ê óâåëè÷åíèþ ñèíòåçà ÐÒÍ. Íàïðìåð, ó ìûøåé ñ îòñóòñòâèåì Klotho Na+/K+-ATPàçà-çàâèñèìîé ñòèìóëÿöèè ÐÒÍ íèçêèì ñîäåðæàíèåì âíåêëåòî÷íîãî Ca ïðàêòè÷åñêè íå ïðîèñõîäèò, â îòëè÷èå îò æèâîòíûõ ñ íîðìàëüíûì óðîâíåì Klotho [36].

35
Drueke TB. Klotho, FGF23, and FGF receptors in chronic kidney disease: a yin-yang situation? Kidney Int. 2010; 78 (11): 1057-1060
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  1. In-text reference with the coordinate start=18683
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    Èçâåñòíî, ÷òî Klotho ìîæåò íåçàâèñèìî îò FGF23 ìîäóëèðîâàòü ñåêðåöèþ PTH: êîñâåííî – ÷åðåç òóáóëÿðíóþ ðåàáñîðáöèþ Ñà è CaSR [34] è ïðÿìî – ÷åðåç âîçäåéñòâèå íà Na+/K+-ATP-àçíóþ àêòèâíîñòü â ÏÙÆ
    Exact
    [35]
    Suffix
    . Ïîñëåäíèé ìåõàíèçì, â îòëè÷èå îò ïðÿìîãî ýôôåêòà FGF23 íà ÏÙÆ, ïðèâîäèò ê óâåëè÷åíèþ ñèíòåçà ÐÒÍ. Íàïðìåð, ó ìûøåé ñ îòñóòñòâèåì Klotho Na+/K+-ATPàçà-çàâèñèìîé ñòèìóëÿöèè ÐÒÍ íèçêèì ñîäåðæàíèåì âíåêëåòî÷íîãî Ca ïðàêòè÷åñêè íå ïðîèñõîäèò, â îòëè÷èå îò æèâîòíûõ ñ íîðìàëüíûì óðîâíåì Klotho [36].

36
Imura A, Tsuji Y, Murata M et al. a-Klotho as a regulator of calcium homeostasis. Science 2007; 316 (5831): 1615–1618
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  1. In-text reference with the coordinate start=18979
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    Ïîñëåäíèé ìåõàíèçì, â îòëè÷èå îò ïðÿìîãî ýôôåêòà FGF23 íà ÏÙÆ, ïðèâîäèò ê óâåëè÷åíèþ ñèíòåçà ÐÒÍ. Íàïðìåð, ó ìûøåé ñ îòñóòñòâèåì Klotho Na+/K+-ATPàçà-çàâèñèìîé ñòèìóëÿöèè ÐÒÍ íèçêèì ñîäåðæàíèåì âíåêëåòî÷íîãî Ca ïðàêòè÷åñêè íå ïðîèñõîäèò, â îòëè÷èå îò æèâîòíûõ ñ íîðìàëüíûì óðîâíåì Klotho
    Exact
    [36]
    Suffix
    . Íåäàâíî òàêæå áûëî óñòàíîâëåíî, ÷òî Klotho îêàçûâàåò íåçàâèñèìîå äåéñòâèå íà îñíîâíîé òðàíñïîðòåð ôîñôàòîâ â ïðîêñèìàëüíûõ êàíàëüöàõ [37]. Òàêèì îáðàçîì, Klotho ïðåäñòàâëÿåò ñîáîé íå òîëüêî êîðåöåïòîð äëÿ ðåàëèçàöèè áèîëîãè÷åñêîãî ýôôåêòà FGF23 â îðãàíàõ-ìèøåíÿõ, íî òàêæå äîïîëíèòåëüíûé ìåõàíèçì åãî êîíòððåãóëÿöèè.

37
Hu MC, Shi M, Zhang J et al. Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J 2010; 24 (9): 3438–3450
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  1. In-text reference with the coordinate start=19119
    Prefix
    Íàïðìåð, ó ìûøåé ñ îòñóòñòâèåì Klotho Na+/K+-ATPàçà-çàâèñèìîé ñòèìóëÿöèè ÐÒÍ íèçêèì ñîäåðæàíèåì âíåêëåòî÷íîãî Ca ïðàêòè÷åñêè íå ïðîèñõîäèò, â îòëè÷èå îò æèâîòíûõ ñ íîðìàëüíûì óðîâíåì Klotho [36]. Íåäàâíî òàêæå áûëî óñòàíîâëåíî, ÷òî Klotho îêàçûâàåò íåçàâèñèìîå äåéñòâèå íà îñíîâíîé òðàíñïîðòåð ôîñôàòîâ â ïðîêñèìàëüíûõ êàíàëüöàõ
    Exact
    [37]
    Suffix
    . Òàêèì îáðàçîì, Klotho ïðåäñòàâëÿåò ñîáîé íå òîëüêî êîðåöåïòîð äëÿ ðåàëèçàöèè áèîëîãè÷åñêîãî ýôôåêòà FGF23 â îðãàíàõ-ìèøåíÿõ, íî òàêæå äîïîëíèòåëüíûé ìåõàíèçì åãî êîíòððåãóëÿöèè. Óñòàíîâëåíî, ÷òî ýêñïðåññèÿ ìàòðè÷íîé ÐÍÊ Klotho â ïî÷êå íà÷èíàåò ñíèæàòüñÿ íà ðàííèõ ñòàäèÿõ ÕÁÏ [38] ïàðàëëåëüíî c óâåëè÷åíèåì FGF23, âïîñëåäñòâèè ïðîãðåññèâíî ñíèæàÿñü äî 5% îò íîðìàëüíîãî óðîâíÿ ó áîëüíûõ íà äèàëèçå

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     òî æå âðåìÿ, îòùåïëåííàÿ âíåêëåòî÷íàÿ ÷àñòü ìîëåêóëû, ïîïàäàÿ â öèðêóëÿöèþ, èìååò íåçàâèñèìûå îò FGF23 ïëåéîòðîïíûå áèîëîãè÷åñêèå ýôôåêòû â âèäå èíãèáèðîâàíèÿ Nà-Ð òðàíñïîðòåðîâ (NPT2a, NPT2c, NPT3) è àêòèâàöèè êàëüöèåâûõ è êàëèåâîãî èîííûõ êàíàëîâ (TRPV5, TRPV6, ROMK1)
    Exact
    [37, 38, 61, 62]
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    . Âåðîÿòíî, ÷òî àêòèâàöèÿ ADAM17 ñâÿçàíà è ñî ñíèæåíèåì ïðîäóêöèè êàëüöèòðèîëà ïðè ÂÃÏÒ, ïîñêîëüêó VDR-àêòèâàòîðû áëîêèðóþò åãî ýêñïðåññèþ, íàðÿäó ñ èíàêòèâàöèåé EGFR [63]. Ñëåäóåò òàêæå îòìåòèòü, ÷òî àêòèâàöèÿ ADAM17, êîòîðàÿ â ïî÷êå ïðîèñõîäèò ïîä äåéñòâèåì àíãèîòåíçèíà II, ìîæåò ïðèâîäèòü ê ïîñëåäñòâèÿì, èìåþùèì ñèñòåìíîå çíà÷åíèå.

38
Hu MC, Shi M, Zhang J et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol 2011; 22 (1): 124–136
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  1. In-text reference with the coordinate start=19402
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    Òàêèì îáðàçîì, Klotho ïðåäñòàâëÿåò ñîáîé íå òîëüêî êîðåöåïòîð äëÿ ðåàëèçàöèè áèîëîãè÷åñêîãî ýôôåêòà FGF23 â îðãàíàõ-ìèøåíÿõ, íî òàêæå äîïîëíèòåëüíûé ìåõàíèçì åãî êîíòððåãóëÿöèè. Óñòàíîâëåíî, ÷òî ýêñïðåññèÿ ìàòðè÷íîé ÐÍÊ Klotho â ïî÷êå íà÷èíàåò ñíèæàòüñÿ íà ðàííèõ ñòàäèÿõ ÕÁÏ
    Exact
    [38]
    Suffix
    ïàðàëëåëüíî c óâåëè÷åíèåì FGF23, âïîñëåäñòâèè ïðîãðåññèâíî ñíèæàÿñü äî 5% îò íîðìàëüíîãî óðîâíÿ ó áîëüíûõ íà äèàëèçå [39]. Åñòü ýêñïåðèìåíòàëüíûå íàáëþäåíèÿ î òîì, ÷òî ñíèæåíèå Klotho ìîæåò ïðåäøåñòâîâàòü ðîñòó FGF-23 increase ïðè ìîäåëèðîâàíèè ðàííèõ ñòàäèé ÕÁÏ [40].

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    Prefix
     òî æå âðåìÿ, îòùåïëåííàÿ âíåêëåòî÷íàÿ ÷àñòü ìîëåêóëû, ïîïàäàÿ â öèðêóëÿöèþ, èìååò íåçàâèñèìûå îò FGF23 ïëåéîòðîïíûå áèîëîãè÷åñêèå ýôôåêòû â âèäå èíãèáèðîâàíèÿ Nà-Ð òðàíñïîðòåðîâ (NPT2a, NPT2c, NPT3) è àêòèâàöèè êàëüöèåâûõ è êàëèåâîãî èîííûõ êàíàëîâ (TRPV5, TRPV6, ROMK1)
    Exact
    [37, 38, 61, 62]
    Suffix
    . Âåðîÿòíî, ÷òî àêòèâàöèÿ ADAM17 ñâÿçàíà è ñî ñíèæåíèåì ïðîäóêöèè êàëüöèòðèîëà ïðè ÂÃÏÒ, ïîñêîëüêó VDR-àêòèâàòîðû áëîêèðóþò åãî ýêñïðåññèþ, íàðÿäó ñ èíàêòèâàöèåé EGFR [63]. Ñëåäóåò òàêæå îòìåòèòü, ÷òî àêòèâàöèÿ ADAM17, êîòîðàÿ â ïî÷êå ïðîèñõîäèò ïîä äåéñòâèåì àíãèîòåíçèíà II, ìîæåò ïðèâîäèòü ê ïîñëåäñòâèÿì, èìåþùèì ñèñòåìíîå çíà÷åíèå.

  3. In-text reference with the coordinate start=29847
    Prefix
    Òàê, â ðÿäå äîñòàòî÷íî êðóïíûõ îáñåðâàöèîííûõ èññëåäîâàíèé ïðîäåìîíòðèðîâàíî, ÷òî ïîâûøåíèå FGF23 ñâÿçàíî ñ íàðóøåíèÿìè ýíäîòåëèÿ, âûðàæåííîñòüþ àòåðîñêëåðîçà, ãèïåðòðîôèåé ìèîêàðäà, ñîñóäèñòîé êàëüöèôèêàöèåé
    Exact
    [38, 71–75]
    Suffix
    . Öèðóëèðóþùàÿ ôîðìà Klotho îáëàäàåò ñïîñîáíîñòüþ ñíèæàòü îêñèäàòèâíûå ïðîöåññû ÷åðåç àêòèâàöèþ FoxO è óâåëè÷åíèå ýêñïðåññèè ñóïåðîêñèääèñìóòàçû [76]. Ïî-âèäèìîìó, Klotho âîâëå÷åí â ïðîöåññû ýíäîòåëèàëüíîé èíòåãðàöèè è ôóíêöèè [77, 78].

39
Koh N, Fujimori T, Nishiguchi S et al. Severely reduced production of klotho in human chronic renal failure kidney. Biochem Biophys Res Commun 2001; 280 (4): 1015–1020
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    Óñòàíîâëåíî, ÷òî ýêñïðåññèÿ ìàòðè÷íîé ÐÍÊ Klotho â ïî÷êå íà÷èíàåò ñíèæàòüñÿ íà ðàííèõ ñòàäèÿõ ÕÁÏ [38] ïàðàëëåëüíî c óâåëè÷åíèåì FGF23, âïîñëåäñòâèè ïðîãðåññèâíî ñíèæàÿñü äî 5% îò íîðìàëüíîãî óðîâíÿ ó áîëüíûõ íà äèàëèçå
    Exact
    [39]
    Suffix
    . Åñòü ýêñïåðèìåíòàëüíûå íàáëþäåíèÿ î òîì, ÷òî ñíèæåíèå Klotho ìîæåò ïðåäøåñòâîâàòü ðîñòó FGF-23 increase ïðè ìîäåëèðîâàíèè ðàííèõ ñòàäèé ÕÁÏ [40]. Ýòè äàííûå è ðÿä äðóãèõ, ÷àñòè÷íî îáñóæäàåìûõ íèæå, ñ ó÷åòîì ñèñòåìíûõ áèîëîãè÷åñêèõ ýôôåêòîâ Klotho, ïîçâîëÿþò íåêîòîðûì àâòîðàì ôîðìóëèðîâàòü «Klotho-öåíòðè÷åñêèå» ãèïîòåçû î ïåðâè÷íîñòè ñíèæåíèÿ ýòîãî áåëêà â ðàçâèòèè êàðäèîðåíàëüíîãî êîíòèíóóìà, êà

40
O’Brien SP, Boulanger JH, Liu S et al. Decline in Klotho expression precedes FGF23 and PTH induction in the Jck mouse, a progressive genetic model of CKD-MBD [Abstract F-FC224]. J Am Soc Nephrol 2009; 20: 54A
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    Óñòàíîâëåíî, ÷òî ýêñïðåññèÿ ìàòðè÷íîé ÐÍÊ Klotho â ïî÷êå íà÷èíàåò ñíèæàòüñÿ íà ðàííèõ ñòàäèÿõ ÕÁÏ [38] ïàðàëëåëüíî c óâåëè÷åíèåì FGF23, âïîñëåäñòâèè ïðîãðåññèâíî ñíèæàÿñü äî 5% îò íîðìàëüíîãî óðîâíÿ ó áîëüíûõ íà äèàëèçå [39]. Åñòü ýêñïåðèìåíòàëüíûå íàáëþäåíèÿ î òîì, ÷òî ñíèæåíèå Klotho ìîæåò ïðåäøåñòâîâàòü ðîñòó FGF-23 increase ïðè ìîäåëèðîâàíèè ðàííèõ ñòàäèé ÕÁÏ
    Exact
    [40]
    Suffix
    . Ýòè äàííûå è ðÿä äðóãèõ, ÷àñòè÷íî îáñóæäàåìûõ íèæå, ñ ó÷åòîì ñèñòåìíûõ áèîëîãè÷åñêèõ ýôôåêòîâ Klotho, ïîçâîëÿþò íåêîòîðûì àâòîðàì ôîðìóëèðîâàòü «Klotho-öåíòðè÷åñêèå» ãèïîòåçû î ïåðâè÷íîñòè ñíèæåíèÿ ýòîãî áåëêà â ðàçâèòèè êàðäèîðåíàëüíîãî êîíòèíóóìà, êàê ìîäåëè ïðåæäåâðåìåííîãî ñòàðåíèÿ [41].

41
Kuro-o М. Phosphate and Klotho. Kidney International 2011; 79 (Suppl 121), S20–S23
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    Ýòè äàííûå è ðÿä äðóãèõ, ÷àñòè÷íî îáñóæäàåìûõ íèæå, ñ ó÷åòîì ñèñòåìíûõ áèîëîãè÷åñêèõ ýôôåêòîâ Klotho, ïîçâîëÿþò íåêîòîðûì àâòîðàì ôîðìóëèðîâàòü «Klotho-öåíòðè÷åñêèå» ãèïîòåçû î ïåðâè÷íîñòè ñíèæåíèÿ ýòîãî áåëêà â ðàçâèòèè êàðäèîðåíàëüíîãî êîíòèíóóìà, êàê ìîäåëè ïðåæäåâðåìåííîãî ñòàðåíèÿ
    Exact
    [41]
    Suffix
    . Ãåíåòè÷åñêèå ìîäåëè.  ýêñïåðèìåíòå äåëåöèè Klotho è FGF23 èìåþò ñõîæèå ôåíîòèïû, êîòîðûå õàðàêòåðèçóþòñÿ ñèñòåìíûìè ïðîÿâëåíèÿìè â âèäå óñêîðåííîãî ñòàðåíèÿ è ãîìåîñòàòè÷åñêèìè ñäâèãàìè, âåñüìà íàïîìèíàþùèìè ðàçâèòèå CKD-MBD.

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    Èíòåðåñíî, ÷òî Klotho îáíàðóæåí â ñèíîàòðèàëüíîì óçëå, à ñíèæåíèå ýêñïðåññèè ýòîãî áåëêà ñâÿçàíî ñ äèñôóíêöèåé ñèíîàòðèàëüíîãî óçëà è ïðåæäåâðåìåííîé ãèáåëüþ ýêñïåðèìåíòàëüíûõ æèâîòíûõ [80]. Ýòè äàííûå ìîãóò èìåòü ïðÿìîå îòíîøåíèå ê êëèíè÷åñêèì ñèòóàöèÿì, ïîñêîëüêó óðîâåíü Klotho îò÷åòëèâî ñíèæåí ó áîëüíûõ ñ ÕÁÏ
    Exact
    [41]
    Suffix
    . Îñíîâíîé ïðîáëåìîé â îöåíêå çíà÷åíèÿ Klotho äëÿ êëèíè÷åñêîé ïðàêòèêè îñòàåòñÿ îòñóòñòâèå ïðîñòûõ è íàäåæíûõ ìåòîäîâ åãî äåòåêöèè. Àêöåíòû ëå÷åáíûõ ñòðàòåãèé.  ñâåòå ïðåäñòàâëåííûõ äàííûõ î÷åâèäíî, ÷òî íà ðàííèõ ñòàäèÿõ ôîðìèðîâàíèÿ ÂÃÏÒ íàèáîëåå ñóùåñòâåííîå çíà÷åíèå èìååò óâåëè÷åíèå ïóëà Ð èç-çà äèñáàëàíñà ìåæäó åãî ïîñòóïëåíèåì è ïî÷å÷íîé ýêñêðåöèåé â óñëîâèÿõ ñíèæåíèÿ ÑÊÔ.

42
Sitara D, Razzaque MS, St-Arnaud R et al. Genetic ablation of vitamin D activation pathway reverses biochemical and skeletal anomalies in Fgf-23-null animals. Am J Pathol 2006; 169 (6): 2161–2170
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    Ïðè ýòîì óðîâåíü êàëüöèòðèîëà ïëàçìû â îòëè÷èå îò ñèòóàöèè ðàçâèòèÿ âòîðè÷íîãî ÃÏÒ ïðè ÕÁÏ ïîâûøåí. Èíòåðåñíî, ÷òî áëîêàäà ñèãíàëüíûõ ïóòåé êàëüöèòðèîëà ïðè èíàêòèâàöèè ãåíà àëüôà-ãèäðîêñèëàçû çíà÷èòåëüíî óìåíüøàëà ïðîÿâëåíèÿ äåôèöèòà FGF23 è Klotho
    Exact
    [42, 43]
    Suffix
    . Ôåíîòèïè÷åñêèå ïðîÿâëåíèÿ íîêàóòà ãåíîâ Klotho è FGF-23 òàêæå â ñóùåñòâåííîé ñòåïåíè óìåíüøàþòñÿ íà ôîíå íèçêîôîñôàòíîé äèåòû ïðè îòñóòñòâèè ñóùåñòâåííîãî âëèÿíèÿ äðóãèõ ãåíåòè÷åñêèõ è äèåòè÷åñêèõ ôàêòîðîâ [44–46].

43
Ohnishi M, Nakatani T, Lanske B et al. Reversal of mineral ion homeostasis and soft-tissue calcification of klotho knockout mice by deletion of vitamin D 1alpha-hydroxylase. Kidney Int 2009; 75 (11): 1166–1172
Total in-text references: 1
  1. In-text reference with the coordinate start=20572
    Prefix
    Ïðè ýòîì óðîâåíü êàëüöèòðèîëà ïëàçìû â îòëè÷èå îò ñèòóàöèè ðàçâèòèÿ âòîðè÷íîãî ÃÏÒ ïðè ÕÁÏ ïîâûøåí. Èíòåðåñíî, ÷òî áëîêàäà ñèãíàëüíûõ ïóòåé êàëüöèòðèîëà ïðè èíàêòèâàöèè ãåíà àëüôà-ãèäðîêñèëàçû çíà÷èòåëüíî óìåíüøàëà ïðîÿâëåíèÿ äåôèöèòà FGF23 è Klotho
    Exact
    [42, 43]
    Suffix
    . Ôåíîòèïè÷åñêèå ïðîÿâëåíèÿ íîêàóòà ãåíîâ Klotho è FGF-23 òàêæå â ñóùåñòâåííîé ñòåïåíè óìåíüøàþòñÿ íà ôîíå íèçêîôîñôàòíîé äèåòû ïðè îòñóòñòâèè ñóùåñòâåííîãî âëèÿíèÿ äðóãèõ ãåíåòè÷åñêèõ è äèåòè÷åñêèõ ôàêòîðîâ [44–46].

44
Morishita K, Shirai A, Kubota M et al. The progression of aging in klotho mutant mice can be modified by dietary phosphorus and zinc. J Nutr 2001; 131 (12): 3182–3188
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    Prefix
    Ôåíîòèïè÷åñêèå ïðîÿâëåíèÿ íîêàóòà ãåíîâ Klotho è FGF-23 òàêæå â ñóùåñòâåííîé ñòåïåíè óìåíüøàþòñÿ íà ôîíå íèçêîôîñôàòíîé äèåòû ïðè îòñóòñòâèè ñóùåñòâåííîãî âëèÿíèÿ äðóãèõ ãåíåòè÷åñêèõ è äèåòè÷åñêèõ ôàêòîðîâ
    Exact
    [44–46]
    Suffix
    . Ñòðóêòóðíàÿ ïåðåñòðîéêà è ðåöåïòîðíûé àïïàðàò ÏÙÆ ïðè ÂÃÏÒ. Îäèí èç âàæíûõ äëÿ ïîíèìàíèÿ ìåõàíèçìîâ ðàçâèòèÿ ÂÃÏÒ âîïðîñîâ çàêëþ÷àåòñÿ â òîì, ïî÷åìó, íåñìîòðÿ íà ïîâûøåíèå FGF23 íà ðàííèõ ñòàäèÿõ ôîðìèðîâàíèÿ ÂÃÏÒ, ïðîèñõîäèò è óâåëè÷åíèå ñåêðåöèè ÐÒÍ [24].

45
Stubbs JR, Liu S, Tang W et al. Role of hyperphosphatemia and 1,25-dihydroxyvitamin D in vascular calcification and mortality in fibroblastic growth factor 23 null mice. J Am Soc Nephrol 2007; 18 (7): 2116–2124
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    Prefix
    Ôåíîòèïè÷åñêèå ïðîÿâëåíèÿ íîêàóòà ãåíîâ Klotho è FGF-23 òàêæå â ñóùåñòâåííîé ñòåïåíè óìåíüøàþòñÿ íà ôîíå íèçêîôîñôàòíîé äèåòû ïðè îòñóòñòâèè ñóùåñòâåííîãî âëèÿíèÿ äðóãèõ ãåíåòè÷åñêèõ è äèåòè÷åñêèõ ôàêòîðîâ
    Exact
    [44–46]
    Suffix
    . Ñòðóêòóðíàÿ ïåðåñòðîéêà è ðåöåïòîðíûé àïïàðàò ÏÙÆ ïðè ÂÃÏÒ. Îäèí èç âàæíûõ äëÿ ïîíèìàíèÿ ìåõàíèçìîâ ðàçâèòèÿ ÂÃÏÒ âîïðîñîâ çàêëþ÷àåòñÿ â òîì, ïî÷åìó, íåñìîòðÿ íà ïîâûøåíèå FGF23 íà ðàííèõ ñòàäèÿõ ôîðìèðîâàíèÿ ÂÃÏÒ, ïðîèñõîäèò è óâåëè÷åíèå ñåêðåöèè ÐÒÍ [24].

46
Ohnishi M, Nakatani T, Lanske B et al. In vivo genetic evidence for suppressing vascular and soft-tissue calcification through the reduction of serum phosphate levels, even in the presence of high serum calcium and 1,25-dihydroxyvitamin d levels. Circ Cardiovasc Genet 2009; 2 (6): 583–590
Total in-text references: 1
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    Ôåíîòèïè÷åñêèå ïðîÿâëåíèÿ íîêàóòà ãåíîâ Klotho è FGF-23 òàêæå â ñóùåñòâåííîé ñòåïåíè óìåíüøàþòñÿ íà ôîíå íèçêîôîñôàòíîé äèåòû ïðè îòñóòñòâèè ñóùåñòâåííîãî âëèÿíèÿ äðóãèõ ãåíåòè÷åñêèõ è äèåòè÷åñêèõ ôàêòîðîâ
    Exact
    [44–46]
    Suffix
    . Ñòðóêòóðíàÿ ïåðåñòðîéêà è ðåöåïòîðíûé àïïàðàò ÏÙÆ ïðè ÂÃÏÒ. Îäèí èç âàæíûõ äëÿ ïîíèìàíèÿ ìåõàíèçìîâ ðàçâèòèÿ ÂÃÏÒ âîïðîñîâ çàêëþ÷àåòñÿ â òîì, ïî÷åìó, íåñìîòðÿ íà ïîâûøåíèå FGF23 íà ðàííèõ ñòàäèÿõ ôîðìèðîâàíèÿ ÂÃÏÒ, ïðîèñõîäèò è óâåëè÷åíèå ñåêðåöèè ÐÒÍ [24].

47
Galitzer H, Ben-Dov IZ, Silver J et al. Parathyroid cell resistance to fibroblast growth factor 23 in secondary hyperparathyroidism of chronic kidney disease. Kidney Int 2010; 77 (3): 211–218
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    Äðóãîå îáúÿñíåíèå ïàðàëëåëüíîãî ðîñòà è PTH ïðè ÕÁÏ çàêëþ÷àåòñÿ â îòíîñèòåëüíîé ðåçèñòåíòíîñòè ÏÙÆ ê äåéñòâèþ FGF23, êîòîðàÿ â ýêñïåðèìåíòå, ïðè ìîäåëèðîâàíèè ïî÷å÷íîé íåäîñòàòî÷íîñòè ïðîÿâëÿåòñÿ â îòñóòñòâèè ñíèæåíèÿ ÐÒÍ â îòâåò íà ââåäåíèå ðåêîìáèíàíòíîãî FGF23
    Exact
    [47]
    Suffix
    . Ïðè÷èíû ïîäîáíîé ðåçèñòåíòíîñòè, ïîâèäèìîìó, ñëåäóåò èñêàòü â ìîëåêóëÿðíîé è ñòðóêòóðíîé ïåðåñòðîéêå ÏÙÆ, êîòîðûå ñëåäóåò ðàññìàòðèâàòü êàê ìîðôîëîãè÷åñêèé ñóáñòðàò ðàçâèòèÿ è ïðîãðåññèðîâàíèÿ ÂÃÏÒ.

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    Íà ðàííèõ ñòðîêàõ ìîäåëèðîâàíèÿ ïî÷å÷íîé íåäîñòàòî÷íîñòè ïðè ñóáòîòàëüíîé íåôðýêòîìèè ýêñïðåññèÿ Klotho è FGFR, íàïðîòèâ, ìîæåò óâåëè÷èâàòüñÿ, êàê ýòî ïîêàçàíî â äâóõ ýêñïåðèìåíòàëüíûõ èññëåäîâàíèÿõ.  îäíîì èç íèõ íà÷àëüíîå ïîâûøåíèå ýêñïðåññèè Klotho è FGFR ñìåíèëîñü ïî ìåðå ïðîãðåññèðîâàíèÿ óðåìèè-ÂÃÏÒ çàêîíîìåðíûì åå ñíèæåíèåì
    Exact
    [47]
    Suffix
    .  äðóãîì – ïîâûøåíèå ýêñïðåññèè Klotho/FGFR1,3 áûëî íåçíà÷èòåëüíûì ïðè óìåðåííîé äèñôóíêöèè ïî÷åê/ÂÃÏÒ, íî âûðàæåííûì ïðè ñî÷åòàíèè óðåìèè ñ òÿæåëûì ÂÃÏÒ íà ôîíå ãèïåðôîñôàòíîé äèåòû [52]. Ïðåäïîëîæèòåëüíî, ðàííÿÿ ïåðåñòðîéêà ìèíåðàëüíîãî îáìåíà ïðè ÕÁÏ îïîñðåäóåòñÿ àêòèâàöèåé Klotho/FGFR1,3, êîòîðàÿ ïî ìåðå ïðîãðåññèðîâàíèÿ ÂÃÏÒ ñìåíÿåòñÿ ñíèæåíèåì èõ ýêñïðåññèè, íàðÿäó ñî ñíèæåíèåì ýêñïðåññèè

48
Komaba H, Goto S, Fujii H et al. Depressed expression of Klotho and FGF receptor 1 in hyperplastic parathyroid glands from uremic patients. Kidney Int 2010; 77 (3): 232–238
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    Ïðîëèôåðàòèâíûå è ãèïåðïëàñòè÷åñêèå ïðîöåññû â ÏÙÆ ïî ìåðå ïðîãðåññèðîâàíèÿ ÂÃÏÒ ñîïðîâîæäàþòñÿ ñíèæåíèåì îñíîâíûõ òèïîâ ðåöåïòîðîâ, ó÷àñòâóþùèõ â ðåãóëÿöèè Ñà-Ð-îáìåíà: ÑaSR è VDR. Ñíèæåíèå ýêñïðåññèè FGFR è Klotho áûëî òàêæå îòìå÷åíî ó áîëüíûõ ñ ÕÁÏ, íà äèàëèçå îñîáåííî ïðè íîäóëÿðíîé ãèïåðïëàçèè ÏÙÆ, ñîïðîâîæäàâøåéñÿ âûñîêîé ýêñïðåññèåé ìàðêåðà ïðîëèôåðàöèè Ki67
    Exact
    [48]
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    , à òàêæå ó ïðåääèàëèçíûõ áîëüíûõ è ïîñëå òðàíñïëàíòàöèè ïî÷êè [49]. Ýòî âàæíûé ìîìåíò â ðàçâèòèè ÂÃÏÒ, òàê êàê FGF23 ðåàëèçóåò ñâîè ýôôåêòû, â òîì ÷èñëå ñíèæàåò ýêñïðåññèþ ãåíà è ñåêðåöèþ ÏÒÃ, äåéñòâóÿ èñêëþ÷èòåëüíî ÷åðåç ñâÿçûâàíèå ñî ñâîèì ñïåöèôè÷åñêèì ðåöåïòîðîì (FGFR1) â ïðèñóòñòâèè åãî êî-ðåöåïòîðà Klotho.

49
Krajisnik T, Olauson H, Mirza MA et al. Parathyroid Klotho and FGF-receptor 1 expression decline with renal function in hyperparathyroid patients with chronic kidney disease and kidney transplant recipients. Kidney Int 2010; 78 (10): 10241032
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    Ñíèæåíèå ýêñïðåññèè FGFR è Klotho áûëî òàêæå îòìå÷åíî ó áîëüíûõ ñ ÕÁÏ, íà äèàëèçå îñîáåííî ïðè íîäóëÿðíîé ãèïåðïëàçèè ÏÙÆ, ñîïðîâîæäàâøåéñÿ âûñîêîé ýêñïðåññèåé ìàðêåðà ïðîëèôåðàöèè Ki67 [48], à òàêæå ó ïðåääèàëèçíûõ áîëüíûõ è ïîñëå òðàíñïëàíòàöèè ïî÷êè
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    . Ýòî âàæíûé ìîìåíò â ðàçâèòèè ÂÃÏÒ, òàê êàê FGF23 ðåàëèçóåò ñâîè ýôôåêòû, â òîì ÷èñëå ñíèæàåò ýêñïðåññèþ ãåíà è ñåêðåöèþ ÏÒÃ, äåéñòâóÿ èñêëþ÷èòåëüíî ÷åðåç ñâÿçûâàíèå ñî ñâîèì ñïåöèôè÷åñêèì ðåöåïòîðîì (FGFR1) â ïðèñóòñòâèè åãî êî-ðåöåïòîðà Klotho.

50
Krajisnik T, Bjorklund P, Marsell R et al. Fibroblast growth factor-23 regulates parathyroid hormone and 1alphahydroxylase expression in cultured bovine parathyroid cells. J Endocrinol 2007; 195: 125–131
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    Ýòî âàæíûé ìîìåíò â ðàçâèòèè ÂÃÏÒ, òàê êàê FGF23 ðåàëèçóåò ñâîè ýôôåêòû, â òîì ÷èñëå ñíèæàåò ýêñïðåññèþ ãåíà è ñåêðåöèþ ÏÒÃ, äåéñòâóÿ èñêëþ÷èòåëüíî ÷åðåç ñâÿçûâàíèå ñî ñâîèì ñïåöèôè÷åñêèì ðåöåïòîðîì (FGFR1) â ïðèñóòñòâèè åãî êî-ðåöåïòîðà Klotho. Íàáëþäàåìàÿ â ýêñïåðèìåíòå è êëèíèêå ñíèæåííàÿ ýêñïðåññèÿ Klotho è FGFR1 ìîæåò ñëóæèòü îäíèì èç îáúÿñíåíèé ðåçèñòåíòíîñòè ÏÙÆ ê FGF23 ïðè ÕÁÏ
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    , êàê ýòî ñëó÷àåòñÿ ïðè èíàêòèâèðóþùèõ ìóòàöèÿõ Klotho ñ ðàçâèòèåì ñåìåéíîãî ãèïåðôîñôàòåìè÷åñêîãî êàëüöèíîçà [51]. Âìåñòå ñ òåì, íîäóëÿðíàÿ ãèïåðïëàçèÿ ÏÙÆ, àññîöèèðóþùàÿñÿ ñî ñíèæåíèåì ýêñïðåññèè ðåöåïòîðîâ VDR, CaSR, FGFR, â îñíîâíîì êàñàåòñÿ äàëåêî çàøåäøèõ ñòàäèé ïî÷å÷íîé äèñôóíêöèè.

51
Ichikawa S, Imel EA, Kreiter ML et al. A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest 2007; 117 (9): 2684–2691
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    Íàáëþäàåìàÿ â ýêñïåðèìåíòå è êëèíèêå ñíèæåííàÿ ýêñïðåññèÿ Klotho è FGFR1 ìîæåò ñëóæèòü îäíèì èç îáúÿñíåíèé ðåçèñòåíòíîñòè ÏÙÆ ê FGF23 ïðè ÕÁÏ [50], êàê ýòî ñëó÷àåòñÿ ïðè èíàêòèâèðóþùèõ ìóòàöèÿõ Klotho ñ ðàçâèòèåì ñåìåéíîãî ãèïåðôîñôàòåìè÷åñêîãî êàëüöèíîçà
    Exact
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    . Âìåñòå ñ òåì, íîäóëÿðíàÿ ãèïåðïëàçèÿ ÏÙÆ, àññîöèèðóþùàÿñÿ ñî ñíèæåíèåì ýêñïðåññèè ðåöåïòîðîâ VDR, CaSR, FGFR, â îñíîâíîì êàñàåòñÿ äàëåêî çàøåäøèõ ñòàäèé ïî÷å÷íîé äèñôóíêöèè. Íà ðàííèõ ñòðîêàõ ìîäåëèðîâàíèÿ ïî÷å÷íîé íåäîñòàòî÷íîñòè ïðè ñóáòîòàëüíîé íåôðýêòîìèè ýêñïðåññèÿ Klotho è FGFR, íàïðîòèâ, ìîæåò óâåëè÷èâàòüñÿ, êàê ýòî ïîêàçàíî â äâóõ ýêñïåðèìåíòàëüíûõ èññëåäîâàíèÿõ.

52
Hofman-Bang J, Martuseviciene G, Santini MA et al. Increased parathyroid expression of klotho in uremic rats. Kidney Int 2010; 78 (11): 1119–1127
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     îäíîì èç íèõ íà÷àëüíîå ïîâûøåíèå ýêñïðåññèè Klotho è FGFR ñìåíèëîñü ïî ìåðå ïðîãðåññèðîâàíèÿ óðåìèè-ÂÃÏÒ çàêîíîìåðíûì åå ñíèæåíèåì [47].  äðóãîì – ïîâûøåíèå ýêñïðåññèè Klotho/FGFR1,3 áûëî íåçíà÷èòåëüíûì ïðè óìåðåííîé äèñôóíêöèè ïî÷åê/ÂÃÏÒ, íî âûðàæåííûì ïðè ñî÷åòàíèè óðåìèè ñ òÿæåëûì ÂÃÏÒ íà ôîíå ãèïåðôîñôàòíîé äèåòû
    Exact
    [52]
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    . Ïðåäïîëîæèòåëüíî, ðàííÿÿ ïåðåñòðîéêà ìèíåðàëüíîãî îáìåíà ïðè ÕÁÏ îïîñðåäóåòñÿ àêòèâàöèåé Klotho/FGFR1,3, êîòîðàÿ ïî ìåðå ïðîãðåññèðîâàíèÿ ÂÃÏÒ ñìåíÿåòñÿ ñíèæåíèåì èõ ýêñïðåññèè, íàðÿäó ñî ñíèæåíèåì ýêñïðåññèè VDR, CaSR è óñèëåíèåì ïðîëèôåðàöèè ÏÙÆ.

53
Wetmore JB, Liu S, Krebill R et al. Effects of cinacalcet and concurrent low-dose vitamin D on FGF23 levels in ESRD. CJASN 2010; 5 (1): 110-116
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    Âçàèìîäåéñòâóåò ëè Klotho/ FGF23/FGFR1 ñ CaSR – îñíîâíûì ðåãóëÿòîðîì ñåêðåöèè PTH – ïîêà íåèçâåñòíî. Îäíàêî èìåþòñÿ ïðåäâàðèòåëüíûå äàííûå î òîì, ÷òî àëëîñòåðè÷åñêàÿ àêòèâàöèÿ CaSR ïðèâîäèò ê ñíèæåíèþ FGF23
    Exact
    [53]
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    . Ìîëåêóëÿðíûå ìåõàíèçìû óñèëåíèÿ ïðîöåññîâ êëåòî÷íîé ïðîëèôåðàöèè è óìåíüøåíèÿ ýêñïðåññèè ðåöåïòîðîâ ÏÙÆ ïðè ÂÃÏÒ äî ñèõ ïîð ïîëíîñòüþ íå äåòàëèçèðîâàíû. Ìîæíî ïðåäïîëàãàòü íàëè÷èå â ÏÙÆ íåêèõ âíóòðèêëåòî÷íûõ ïóòåé, îáùèõ äëÿ ïåðåäà÷è ðàçëè÷íûõ âíåêëåòî÷íûõ ñèãíàëîâ, òàêèõ êàê èçìåíåíèÿ êîíöåíòðàöèè Ñà, Ð, 1,25(OH)2D3 è FGF23/FGFR/Klotho, íàïðàâëåííûõ è íà ðåãóëÿöèþ ãåíîìíîé ýêñïðåññèè PTH, åãî ñ

54
Dusso AS, Pavlopoulos T, Naumovich L et al. p21WAF1 and transforming growth factor-б mediate dietary phosphate regulation of parathyroid cell growth. Kidney Int 2001; 59 (3): 855–865
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  1. In-text reference with the coordinate start=26018
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    Dusso è ñîàâò. ïîêàçàíî, ÷òî íà ðàííèõ ñòàäèÿõ ÕÁÏ îãðàíè÷åíèå ïîòðåáëåíèÿ Ð áëîêèðóåò ðàçâèòèå ãèïåðïëàçèè ÏÙÆ â ðåçóëüòàòå ñïåöèôè÷åñêîé èíäóêöèè ìÐÍÊ è ñèíòåçà ð21-èíãèáèòîðà öèêëèí-çàâèñèìîé êèíàçû. Êðîìå òîãî, âûñîêîôîñôàòíàÿ äèåòà èíäóöèðîâàëà òðàíñôîðìèðóþùèé ôàêòîð ðîñòà àëüôà (TGF-α), êîòîðûé, âåðîÿòíî, ÿâëÿåòñÿ àóòîêðèííûì ñèãíàëîì ñòèìóëÿöèè êëåòî÷íîãî ðîñòà è ãèïåðïëàçèè ÏÙÆ
    Exact
    [54]
    Suffix
    . Äåéñòâèå TGF-α îïîñðåäîâàíî àêòèâàöèåé ðåöåïòîðà ýïèäåðìàëüíîãî ôàêòîðà ðîñòà (EGFR) – ìåìáðàííîãî ãëèêîïðîòåèíà ñ òèðîçèíêèíàçíîé àêòèâíîñòüþ, êîòîðûé ïðè òðàíñëîêàöèè â ÿäðî ðàáîòàåò êàê òðàíñêðèïöèîííûé ôàêòîð [55].

55
Wells A. EGF receptor. Int J Biochem Cell Biol 1999; 31: 637–643
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    Äåéñòâèå TGF-α îïîñðåäîâàíî àêòèâàöèåé ðåöåïòîðà ýïèäåðìàëüíîãî ôàêòîðà ðîñòà (EGFR) – ìåìáðàííîãî ãëèêîïðîòåèíà ñ òèðîçèíêèíàçíîé àêòèâíîñòüþ, êîòîðûé ïðè òðàíñëîêàöèè â ÿäðî ðàáîòàåò êàê òðàíñêðèïöèîííûé ôàêòîð
    Exact
    [55]
    Suffix
    .  ðÿäå èññëåäîâàíèé âûÿâëåíî, ÷òî óâåëè÷åíèå ïîòðåáëåíèÿ Ð (è ñíèæåíèå Ñà) ïðè ýêñïåðèìåíòàëüíîì ìîäåëèðîâàíèè ÕÁÏ ïðèâîäèò ê óâåëè÷åíèþ è TGF-α, è EGFR, à áëîêàäà òèðîçèíêèíàçíîé àêòèâíîñòè äàåò îáðàòíûé ýôôåêò [56].

56
Cozzolino M, Lu Y, Sato T et al. A critical role for enhanced TGF-a and EGFR expression in the initiation of parathyroid hyperplasia in experimental kidney disease. Am J Physiol Renal Physiol 2005; 289 (5): F1096–F1102
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     ðÿäå èññëåäîâàíèé âûÿâëåíî, ÷òî óâåëè÷åíèå ïîòðåáëåíèÿ Ð (è ñíèæåíèå Ñà) ïðè ýêñïåðèìåíòàëüíîì ìîäåëèðîâàíèè ÕÁÏ ïðèâîäèò ê óâåëè÷åíèþ è TGF-α, è EGFR, à áëîêàäà òèðîçèíêèíàçíîé àêòèâíîñòè äàåò îáðàòíûé ýôôåêò
    Exact
    [56]
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    . Àêòèâàöèÿ ñèñòåìû TGF-α/EGFR òàêæå îïðåäåëåííî àññîöèèðóåòñÿ îäíîâðåìåííî ñ äâóìÿ ñîáûòèÿìè — ãèïåðïëàçèåé ÏÙÆ è ñíèæåíèåì ýêñïðåññèè VDR. Ïðè ýòîì ïåðåäà÷à ñèãíàëà â ÿäðî êëåòêè îñóùåñòâëÿåòñÿ ÷åðåç LIP (liver-enriched inhibitory protein), ÿâëÿþùèìñÿ ìîùíûì ìèòîãåíîì è äåéñòâóþùèì íà òðàíñêðèïöèþ ãåíîâ [57].

57
Raught B, Gingras AC, James A et al. Expression of a translationally regulated, dominant-negative CCAAT/enhancerbinding protein beta isoform and up-regulation of the eukaryotic translation initiation factor 2alpha are correlated with neoplastic transformation of mammary epithelial cells. Cancer Res 1996; 56 (19): 4382–4386
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    Àêòèâàöèÿ ñèñòåìû TGF-α/EGFR òàêæå îïðåäåëåííî àññîöèèðóåòñÿ îäíîâðåìåííî ñ äâóìÿ ñîáûòèÿìè — ãèïåðïëàçèåé ÏÙÆ è ñíèæåíèåì ýêñïðåññèè VDR. Ïðè ýòîì ïåðåäà÷à ñèãíàëà â ÿäðî êëåòêè îñóùåñòâëÿåòñÿ ÷åðåç LIP (liver-enriched inhibitory protein), ÿâëÿþùèìñÿ ìîùíûì ìèòîãåíîì è äåéñòâóþùèì íà òðàíñêðèïöèþ ãåíîâ
    Exact
    [57]
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    . Ïîñêîëüêó ñíèæåíèå ýêñïðåñèè VDR â ÏÙÆ ÿâëÿåòñÿ ðåãóëüòàòîì LIP-àêòèâèðóåìîãî ñíèæåíèÿ òðàíñêðèïöèè ãåíà VDR [58], òî ìîæíî ïðåäïîëîæèòü, ÷òî ýòîò ÿäåðíûé ìåõàíèçì îïîñðåäóåò òàêæå ñíèæåíèå ýêñïðåññèè CaSR, FGFR è Klotho.

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Arcidiacono MV, Sato T, Alvarez-Hernandez D et al. EGFR activation increases parathyroid hyperplasia and calcitriol resistance in kidney disease. J Am Soc Nephrol 2008; 19 (2): 310-320
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    Ïðè ýòîì ïåðåäà÷à ñèãíàëà â ÿäðî êëåòêè îñóùåñòâëÿåòñÿ ÷åðåç LIP (liver-enriched inhibitory protein), ÿâëÿþùèìñÿ ìîùíûì ìèòîãåíîì è äåéñòâóþùèì íà òðàíñêðèïöèþ ãåíîâ [57]. Ïîñêîëüêó ñíèæåíèå ýêñïðåñèè VDR â ÏÙÆ ÿâëÿåòñÿ ðåãóëüòàòîì LIP-àêòèâèðóåìîãî ñíèæåíèÿ òðàíñêðèïöèè ãåíà VDR
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    , òî ìîæíî ïðåäïîëîæèòü, ÷òî ýòîò ÿäåðíûé ìåõàíèçì îïîñðåäóåò òàêæå ñíèæåíèå ýêñïðåññèè CaSR, FGFR è Klotho. Åùå îäíèì ìîëåêóëÿðíûì ìåõàíèçìîì, ñâÿçûâàþùèì ãèïåðôîñôàòåìèþ è ïàòîìîðôîëîãè÷åñêîå èçìåíåíèå ïðè ÂÃÏÒ ÿâëÿþòñÿ TNF-α (ëèãàíä EGFR) è åãî êîíâåðòàçà (TACE èëè ADAM17 ) – ìåòàëëîïðîòåèíàçà, çàïóñêàþùàÿ ñèãíàëüíûå ïóòè TGF-α è íåêîòîðûõ äðóãèõ ëèãàíäîâ.

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Dusso A, Arcidiacono MV, Yang J et al. Vitamin D inhibition of TACE and prevention of renal osteodystrophy and cardiovascular mortality. J Steroid Biochem Mol Biol 2010; 121 (1-2): 193–198
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    ìîëåêóëÿðíûì ìåõàíèçìîì, ñâÿçûâàþùèì ãèïåðôîñôàòåìèþ è ïàòîìîðôîëîãè÷åñêîå èçìåíåíèå ïðè ÂÃÏÒ ÿâëÿþòñÿ TNF-α (ëèãàíä EGFR) è åãî êîíâåðòàçà (TACE èëè ADAM17 ) – ìåòàëëîïðîòåèíàçà, çàïóñêàþùàÿ ñèãíàëüíûå ïóòè TGF-α è íåêîòîðûõ äðóãèõ ëèãàíäîâ. Òàê, åñòü ïåðåäâàðèòåëüíûå äàííûå î òîì, ÷òî â ìîäåëè óðåìèè âûñîêîôîñôàòíàÿ äèåòà ïðèâîäèëà ê óâåëè÷åíèþ îáðàçîâàíèÿ ADAM17 â ÏÙÆ íà ðàííèõ ñòàäèÿõ ÂÏÒÃ
    Exact
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    . Èíòåðåñíî, ÷òî ADAM17, íàðÿäó ñ äðóãèìè ìåìáðàííûìè ïðîòåàçàìè (BACE1, ADAM10), ïî-âèäèìîìó, ìîæåò ïðèíèìàòü ó÷àñòèå â îãðàíè÷åííîì ïðîòåîëèçå áåëêà Klotho [60]. Ïðè ýòîì, ïîñëåäíèé, ïî-âèäèìîìó, óòðà÷èâàåò ñâîè ðåöåïòîðíûå ñâîéñòâà, ôîðìèðóÿ ðàçâèòèå FGF23-ðåçèñòåíòíîñòè îðãàíîâ-ìèøåíåé.

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Chen CD, Podvin S, Gillespie E et al. Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc Natl Acad Sci USA 2007; 104 (50): 19796–19801
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    Òàê, åñòü ïåðåäâàðèòåëüíûå äàííûå î òîì, ÷òî â ìîäåëè óðåìèè âûñîêîôîñôàòíàÿ äèåòà ïðèâîäèëà ê óâåëè÷åíèþ îáðàçîâàíèÿ ADAM17 â ÏÙÆ íà ðàííèõ ñòàäèÿõ ÂÏÒà [59]. Èíòåðåñíî, ÷òî ADAM17, íàðÿäó ñ äðóãèìè ìåìáðàííûìè ïðîòåàçàìè (BACE1, ADAM10), ïî-âèäèìîìó, ìîæåò ïðèíèìàòü ó÷àñòèå â îãðàíè÷åííîì ïðîòåîëèçå áåëêà Klotho
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    [60]
    Suffix
    . Ïðè ýòîì, ïîñëåäíèé, ïî-âèäèìîìó, óòðà÷èâàåò ñâîè ðåöåïòîðíûå ñâîéñòâà, ôîðìèðóÿ ðàçâèòèå FGF23-ðåçèñòåíòíîñòè îðãàíîâ-ìèøåíåé.  òî æå âðåìÿ, îòùåïëåííàÿ âíåêëåòî÷íàÿ ÷àñòü ìîëåêóëû, ïîïàäàÿ â öèðêóëÿöèþ, èìååò íåçàâèñèìûå îò FGF23 ïëåéîòðîïíûå áèîëîãè÷åñêèå ýôôåêòû â âèäå èíãèáèðîâàíèÿ Nà-Ð òðàíñïîðòåðîâ (NPT2a, NPT2c, NPT3) è àêòèâàöèè êàëüöèåâûõ è êàëèåâîãî èîííûõ êàíàëîâ (TRPV5, TRPV6, ROMK

61
Bloch L, Sineshchekova O, Reichenbach D et al. Klotho is a substrate for a-, в- and г-secretase. FEBS Lett 2009; 583 (19): 3221–3224
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    Prefix
     òî æå âðåìÿ, îòùåïëåííàÿ âíåêëåòî÷íàÿ ÷àñòü ìîëåêóëû, ïîïàäàÿ â öèðêóëÿöèþ, èìååò íåçàâèñèìûå îò FGF23 ïëåéîòðîïíûå áèîëîãè÷åñêèå ýôôåêòû â âèäå èíãèáèðîâàíèÿ Nà-Ð òðàíñïîðòåðîâ (NPT2a, NPT2c, NPT3) è àêòèâàöèè êàëüöèåâûõ è êàëèåâîãî èîííûõ êàíàëîâ (TRPV5, TRPV6, ROMK1)
    Exact
    [37, 38, 61, 62]
    Suffix
    . Âåðîÿòíî, ÷òî àêòèâàöèÿ ADAM17 ñâÿçàíà è ñî ñíèæåíèåì ïðîäóêöèè êàëüöèòðèîëà ïðè ÂÃÏÒ, ïîñêîëüêó VDR-àêòèâàòîðû áëîêèðóþò åãî ýêñïðåññèþ, íàðÿäó ñ èíàêòèâàöèåé EGFR [63]. Ñëåäóåò òàêæå îòìåòèòü, ÷òî àêòèâàöèÿ ADAM17, êîòîðàÿ â ïî÷êå ïðîèñõîäèò ïîä äåéñòâèåì àíãèîòåíçèíà II, ìîæåò ïðèâîäèòü ê ïîñëåäñòâèÿì, èìåþùèì ñèñòåìíîå çíà÷åíèå.

62
Chen CD, Podvin S, Gillespie E et al. Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc Natl Acad Sci USA 2007; 104 (50): 19796–19801
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  1. In-text reference with the coordinate start=27966
    Prefix
     òî æå âðåìÿ, îòùåïëåííàÿ âíåêëåòî÷íàÿ ÷àñòü ìîëåêóëû, ïîïàäàÿ â öèðêóëÿöèþ, èìååò íåçàâèñèìûå îò FGF23 ïëåéîòðîïíûå áèîëîãè÷åñêèå ýôôåêòû â âèäå èíãèáèðîâàíèÿ Nà-Ð òðàíñïîðòåðîâ (NPT2a, NPT2c, NPT3) è àêòèâàöèè êàëüöèåâûõ è êàëèåâîãî èîííûõ êàíàëîâ (TRPV5, TRPV6, ROMK1)
    Exact
    [37, 38, 61, 62]
    Suffix
    . Âåðîÿòíî, ÷òî àêòèâàöèÿ ADAM17 ñâÿçàíà è ñî ñíèæåíèåì ïðîäóêöèè êàëüöèòðèîëà ïðè ÂÃÏÒ, ïîñêîëüêó VDR-àêòèâàòîðû áëîêèðóþò åãî ýêñïðåññèþ, íàðÿäó ñ èíàêòèâàöèåé EGFR [63]. Ñëåäóåò òàêæå îòìåòèòü, ÷òî àêòèâàöèÿ ADAM17, êîòîðàÿ â ïî÷êå ïðîèñõîäèò ïîä äåéñòâèåì àíãèîòåíçèíà II, ìîæåò ïðèâîäèòü ê ïîñëåäñòâèÿì, èìåþùèì ñèñòåìíîå çíà÷åíèå.

63
Cordero JB, Cozzolino M, Lu Y et al. 1,25Dihydroxyvitamin D down-regulates cell membrane growthand nuclear growth-promoting signals by the epidermal growth factor receptor. J Biol Chem 2002; 277 (41): 38965–38971
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  1. In-text reference with the coordinate start=28149
    Prefix
    â öèðêóëÿöèþ, èìååò íåçàâèñèìûå îò FGF23 ïëåéîòðîïíûå áèîëîãè÷åñêèå ýôôåêòû â âèäå èíãèáèðîâàíèÿ Nà-Ð òðàíñïîðòåðîâ (NPT2a, NPT2c, NPT3) è àêòèâàöèè êàëüöèåâûõ è êàëèåâîãî èîííûõ êàíàëîâ (TRPV5, TRPV6, ROMK1) [37, 38, 61, 62]. Âåðîÿòíî, ÷òî àêòèâàöèÿ ADAM17 ñâÿçàíà è ñî ñíèæåíèåì ïðîäóêöèè êàëüöèòðèîëà ïðè ÂÃÏÒ, ïîñêîëüêó VDR-àêòèâàòîðû áëîêèðóþò åãî ýêñïðåññèþ, íàðÿäó ñ èíàêòèâàöèåé EGFR
    Exact
    [63]
    Suffix
    . Ñëåäóåò òàêæå îòìåòèòü, ÷òî àêòèâàöèÿ ADAM17, êîòîðàÿ â ïî÷êå ïðîèñõîäèò ïîä äåéñòâèåì àíãèîòåíçèíà II, ìîæåò ïðèâîäèòü ê ïîñëåäñòâèÿì, èìåþùèì ñèñòåìíîå çíà÷åíèå. ADAM17-îïîñðåäîâàííîå ëîêàëüíîå âûñâîáîæäåíèå è óâåëè÷åíèå â ñèñòåìíîé öèðêóëÿöèè TNFα, îáðàäàþùåãî èçâåñòíûìè ïðîôèáðîòè÷åñêèìè/ ïðîâîñïàëèòåëüíûìè ñâîéñòâàìè, a òàêæå ìîëåêóë àäãåçèè (ICAM-1 è VCAM-1), ìîæåò èìåòü ïðÿìîå îòíîøåí

64
Dusso A. Kidney disease and vitamin D levels: 25hydroxyvitamin D, 1,25-dihydroxyvitamin D, and VDR activation. Kidney Int 2011; Suppl. 1: 136-141
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  1. In-text reference with the coordinate start=28636
    Prefix
    ADAM17-îïîñðåäîâàííîå ëîêàëüíîå âûñâîáîæäåíèå è óâåëè÷åíèå â ñèñòåìíîé öèðêóëÿöèè TNFα, îáðàäàþùåãî èçâåñòíûìè ïðîôèáðîòè÷åñêèìè/ ïðîâîñïàëèòåëüíûìè ñâîéñòâàìè, a òàêæå ìîëåêóë àäãåçèè (ICAM-1 è VCAM-1), ìîæåò èìåòü ïðÿìîå îòíîøåíèå ê ðàçâèòèþ ñèñòåìíîãî âîñïàëèòåëüíîãî ñòðåññà è ñåðäå÷íî-ñîñóäèñòûõ îñëîæíåíèé
    Exact
    [64]
    Suffix
    . Ïðîëèôåðàòèâíûå ïðîöåññû â ÏÙÆ òàêæå ìîãóò êîíòðîëèðîâàòüñÿ ýêñïðåñèåé Pit-1 – íàòðèéçàâèñèìîãî ôîñôàòíîãî êî-òðàíñïîðòåðà, êîòîðûé, âåðîÿòíî, ÿâëÿåòñÿ ôîñôàòíûì ñåíñîðîì îðãàíà è ðåãóëèðóåòñÿ Ð è êàëüöèòðèîëîì [65].

65
Tatsumi S, Segawa H, Morita K et al. Molecular cloning and hormonal regulation of PiT-1, a sodium-dependent phosphate cotransporter from rat parathyroid glands. Endocrinology 1998; 139 (4):1692-1699
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    Ïðîëèôåðàòèâíûå ïðîöåññû â ÏÙÆ òàêæå ìîãóò êîíòðîëèðîâàòüñÿ ýêñïðåñèåé Pit-1 – íàòðèéçàâèñèìîãî ôîñôàòíîãî êî-òðàíñïîðòåðà, êîòîðûé, âåðîÿòíî, ÿâëÿåòñÿ ôîñôàòíûì ñåíñîðîì îðãàíà è ðåãóëèðóåòñÿ Ð è êàëüöèòðèîëîì
    Exact
    [65]
    Suffix
    . Íåäàâíî ïîêàçàíî, ÷òî ñíèæåíèå ýêñïðåññèè Pit-1 âñëåäñòâèå íàãðóçêè Ð ïðèâîäèò ê óâåëè÷åíèþ ïðîëèôåðàòèâíîãî ñèãíàëà â ÏÙÆ [66]. Äðóãèå ñèñòåìíûå ïîñëåäñòâèÿ èçìåíåíèé â ñèñòåìå FGF-23/Klotho. Âûñîêèé óðîâåíü FGF23 ÿâëÿåòñÿ íåçàâèñèìûì ïðåäèêòîðîì áûñòðîãî ïðîãðåññèðîâàíèÿ ÕÁÏ, êîíêóðèðóþùèì ïî çíà÷èìîñòè ñ ïðîòåèíóðèåé [67, 68].

66
Jiang Y, Wang M. Overexpression of parathyroid pituitary-specific transcription factor (Pit)-1 in hyperphosphatemia-induced hyperparathyroidism of chronic renal failure rats. Chin Med J (Engl) 2010;123 (12): 1566-1570
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    Ïðîëèôåðàòèâíûå ïðîöåññû â ÏÙÆ òàêæå ìîãóò êîíòðîëèðîâàòüñÿ ýêñïðåñèåé Pit-1 – íàòðèéçàâèñèìîãî ôîñôàòíîãî êî-òðàíñïîðòåðà, êîòîðûé, âåðîÿòíî, ÿâëÿåòñÿ ôîñôàòíûì ñåíñîðîì îðãàíà è ðåãóëèðóåòñÿ Ð è êàëüöèòðèîëîì [65]. Íåäàâíî ïîêàçàíî, ÷òî ñíèæåíèå ýêñïðåññèè Pit-1 âñëåäñòâèå íàãðóçêè Ð ïðèâîäèò ê óâåëè÷åíèþ ïðîëèôåðàòèâíîãî ñèãíàëà â ÏÙÆ
    Exact
    [66]
    Suffix
    . Äðóãèå ñèñòåìíûå ïîñëåäñòâèÿ èçìåíåíèé â ñèñòåìå FGF-23/Klotho. Âûñîêèé óðîâåíü FGF23 ÿâëÿåòñÿ íåçàâèñèìûì ïðåäèêòîðîì áûñòðîãî ïðîãðåññèðîâàíèÿ ÕÁÏ, êîíêóðèðóþùèì ïî çíà÷èìîñòè ñ ïðîòåèíóðèåé [67, 68].

67
Fliser D, Kollerits B, Never U et al. Fibroblast growth factor 23 (FGF-23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) Study. J Am Soc Nephrol 2007; 18 (9): 2600–2608
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  1. In-text reference with the coordinate start=29176
    Prefix
    Íåäàâíî ïîêàçàíî, ÷òî ñíèæåíèå ýêñïðåññèè Pit-1 âñëåäñòâèå íàãðóçêè Ð ïðèâîäèò ê óâåëè÷åíèþ ïðîëèôåðàòèâíîãî ñèãíàëà â ÏÙÆ [66]. Äðóãèå ñèñòåìíûå ïîñëåäñòâèÿ èçìåíåíèé â ñèñòåìå FGF-23/Klotho. Âûñîêèé óðîâåíü FGF23 ÿâëÿåòñÿ íåçàâèñèìûì ïðåäèêòîðîì áûñòðîãî ïðîãðåññèðîâàíèÿ ÕÁÏ, êîíêóðèðóþùèì ïî çíà÷èìîñòè ñ ïðîòåèíóðèåé
    Exact
    [67, 68]
    Suffix
    . FGF-23 ïðÿìî ñâÿçàí ñ âûðàæåííîñòüþ ïðîòåèíóðèè [69] è, íåçàâèñèìî îò äðóãèõ êîâàðèàò, áûë àññîöèèðîâàí ñî ñìåðòíîñòüþ ïðè àíàëèçå çíà÷èòåëüíîé ãðóïïû áîëüíûõ íà äèàëèçå [70].  îòíîøåíèè äðóãèõ îðãàíîâ òåîðåòè÷åñêè ìîæíî ïðåäïîëîæèòü, ÷òî â óñëîâèÿõ ñíèæåíèÿ ìàññû äåéñòâóþùèõ íåôðîíîâ è ðåäóêöèè ðåöåïòîðíîãî àïïàðàòà FGF23 åãî äåéñòâèå ìîæåò ðàñïðîñòðàíÿòüñÿ íà ëþáûå äðóãèå òêàíè, ýêñïðåññèðóþù

68
Titan SM, Zatz R, Graciolli FG et al. FGF-23 as a predictor of renal outcome in diabetic nephropathy. Clin J Am Soc Nephrol 2010; 6 (2): 241–247
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  1. In-text reference with the coordinate start=29176
    Prefix
    Íåäàâíî ïîêàçàíî, ÷òî ñíèæåíèå ýêñïðåññèè Pit-1 âñëåäñòâèå íàãðóçêè Ð ïðèâîäèò ê óâåëè÷åíèþ ïðîëèôåðàòèâíîãî ñèãíàëà â ÏÙÆ [66]. Äðóãèå ñèñòåìíûå ïîñëåäñòâèÿ èçìåíåíèé â ñèñòåìå FGF-23/Klotho. Âûñîêèé óðîâåíü FGF23 ÿâëÿåòñÿ íåçàâèñèìûì ïðåäèêòîðîì áûñòðîãî ïðîãðåññèðîâàíèÿ ÕÁÏ, êîíêóðèðóþùèì ïî çíà÷èìîñòè ñ ïðîòåèíóðèåé
    Exact
    [67, 68]
    Suffix
    . FGF-23 ïðÿìî ñâÿçàí ñ âûðàæåííîñòüþ ïðîòåèíóðèè [69] è, íåçàâèñèìî îò äðóãèõ êîâàðèàò, áûë àññîöèèðîâàí ñî ñìåðòíîñòüþ ïðè àíàëèçå çíà÷èòåëüíîé ãðóïïû áîëüíûõ íà äèàëèçå [70].  îòíîøåíèè äðóãèõ îðãàíîâ òåîðåòè÷åñêè ìîæíî ïðåäïîëîæèòü, ÷òî â óñëîâèÿõ ñíèæåíèÿ ìàññû äåéñòâóþùèõ íåôðîíîâ è ðåäóêöèè ðåöåïòîðíîãî àïïàðàòà FGF23 åãî äåéñòâèå ìîæåò ðàñïðîñòðàíÿòüñÿ íà ëþáûå äðóãèå òêàíè, ýêñïðåññèðóþù

69
Vervloet M, van Zuilen AD, Blankenstijn PJ et al. Fibroblast growth factor 23 is associated with proteinuria. J Am Soc Nephrol 2010; 21: 186A
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  1. In-text reference with the coordinate start=29233
    Prefix
    Äðóãèå ñèñòåìíûå ïîñëåäñòâèÿ èçìåíåíèé â ñèñòåìå FGF-23/Klotho. Âûñîêèé óðîâåíü FGF23 ÿâëÿåòñÿ íåçàâèñèìûì ïðåäèêòîðîì áûñòðîãî ïðîãðåññèðîâàíèÿ ÕÁÏ, êîíêóðèðóþùèì ïî çíà÷èìîñòè ñ ïðîòåèíóðèåé [67, 68]. FGF-23 ïðÿìî ñâÿçàí ñ âûðàæåííîñòüþ ïðîòåèíóðèè
    Exact
    [69]
    Suffix
    è, íåçàâèñèìî îò äðóãèõ êîâàðèàò, áûë àññîöèèðîâàí ñî ñìåðòíîñòüþ ïðè àíàëèçå çíà÷èòåëüíîé ãðóïïû áîëüíûõ íà äèàëèçå [70].  îòíîøåíèè äðóãèõ îðãàíîâ òåîðåòè÷åñêè ìîæíî ïðåäïîëîæèòü, ÷òî â óñëîâèÿõ ñíèæåíèÿ ìàññû äåéñòâóþùèõ íåôðîíîâ è ðåäóêöèè ðåöåïòîðíîãî àïïàðàòà FGF23 åãî äåéñòâèå ìîæåò ðàñïðîñòðàíÿòüñÿ íà ëþáûå äðóãèå òêàíè, ýêñïðåññèðóþùèå FGFR è Klotho, âûçûâàÿ ïàòîëîãè÷åñêèå ñäâèãè [71].

70
Gutierrez OM, Mannstadt M, Isakova T et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 2008; 359 (6): 584–592
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  1. In-text reference with the coordinate start=29354
    Prefix
    Âûñîêèé óðîâåíü FGF23 ÿâëÿåòñÿ íåçàâèñèìûì ïðåäèêòîðîì áûñòðîãî ïðîãðåññèðîâàíèÿ ÕÁÏ, êîíêóðèðóþùèì ïî çíà÷èìîñòè ñ ïðîòåèíóðèåé [67, 68]. FGF-23 ïðÿìî ñâÿçàí ñ âûðàæåííîñòüþ ïðîòåèíóðèè [69] è, íåçàâèñèìî îò äðóãèõ êîâàðèàò, áûë àññîöèèðîâàí ñî ñìåðòíîñòüþ ïðè àíàëèçå çíà÷èòåëüíîé ãðóïïû áîëüíûõ íà äèàëèçå
    Exact
    [70]
    Suffix
    .  îòíîøåíèè äðóãèõ îðãàíîâ òåîðåòè÷åñêè ìîæíî ïðåäïîëîæèòü, ÷òî â óñëîâèÿõ ñíèæåíèÿ ìàññû äåéñòâóþùèõ íåôðîíîâ è ðåäóêöèè ðåöåïòîðíîãî àïïàðàòà FGF23 åãî äåéñòâèå ìîæåò ðàñïðîñòðàíÿòüñÿ íà ëþáûå äðóãèå òêàíè, ýêñïðåññèðóþùèå FGFR è Klotho, âûçûâàÿ ïàòîëîãè÷åñêèå ñäâèãè [71].

71
Vervloet M, Larsson T. Fibroblast growth factor-23 and Klotho in chronic kidney disease. Kidney Int 2011; Suppl. 1: 130-135
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  1. In-text reference with the coordinate start=29632
    Prefix
     îòíîøåíèè äðóãèõ îðãàíîâ òåîðåòè÷åñêè ìîæíî ïðåäïîëîæèòü, ÷òî â óñëîâèÿõ ñíèæåíèÿ ìàññû äåéñòâóþùèõ íåôðîíîâ è ðåäóêöèè ðåöåïòîðíîãî àïïàðàòà FGF23 åãî äåéñòâèå ìîæåò ðàñïðîñòðàíÿòüñÿ íà ëþáûå äðóãèå òêàíè, ýêñïðåññèðóþùèå FGFR è Klotho, âûçûâàÿ ïàòîëîãè÷åñêèå ñäâèãè
    Exact
    [71]
    Suffix
    . Òàê, â ðÿäå äîñòàòî÷íî êðóïíûõ îáñåðâàöèîííûõ èññëåäîâàíèé ïðîäåìîíòðèðîâàíî, ÷òî ïîâûøåíèå FGF23 ñâÿçàíî ñ íàðóøåíèÿìè ýíäîòåëèÿ, âûðàæåííîñòüþ àòåðîñêëåðîçà, ãèïåðòðîôèåé ìèîêàðäà, ñîñóäèñòîé êàëüöèôèêàöèåé [38, 71–75].

  2. In-text reference with the coordinate start=29847
    Prefix
    Òàê, â ðÿäå äîñòàòî÷íî êðóïíûõ îáñåðâàöèîííûõ èññëåäîâàíèé ïðîäåìîíòðèðîâàíî, ÷òî ïîâûøåíèå FGF23 ñâÿçàíî ñ íàðóøåíèÿìè ýíäîòåëèÿ, âûðàæåííîñòüþ àòåðîñêëåðîçà, ãèïåðòðîôèåé ìèîêàðäà, ñîñóäèñòîé êàëüöèôèêàöèåé
    Exact
    [38, 71–75]
    Suffix
    . Öèðóëèðóþùàÿ ôîðìà Klotho îáëàäàåò ñïîñîáíîñòüþ ñíèæàòü îêñèäàòèâíûå ïðîöåññû ÷åðåç àêòèâàöèþ FoxO è óâåëè÷åíèå ýêñïðåññèè ñóïåðîêñèääèñìóòàçû [76]. Ïî-âèäèìîìó, Klotho âîâëå÷åí â ïðîöåññû ýíäîòåëèàëüíîé èíòåãðàöèè è ôóíêöèè [77, 78].

72
Mirza MA, Larsson A, Lind L et al. Circulating fibroblast growth factor-23 is associated with vascular dysfunction in the community. Atherosclerosis 2009; 205 (2): 385–390
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  1. In-text reference with the coordinate start=29847
    Prefix
    Òàê, â ðÿäå äîñòàòî÷íî êðóïíûõ îáñåðâàöèîííûõ èññëåäîâàíèé ïðîäåìîíòðèðîâàíî, ÷òî ïîâûøåíèå FGF23 ñâÿçàíî ñ íàðóøåíèÿìè ýíäîòåëèÿ, âûðàæåííîñòüþ àòåðîñêëåðîçà, ãèïåðòðîôèåé ìèîêàðäà, ñîñóäèñòîé êàëüöèôèêàöèåé
    Exact
    [38, 71–75]
    Suffix
    . Öèðóëèðóþùàÿ ôîðìà Klotho îáëàäàåò ñïîñîáíîñòüþ ñíèæàòü îêñèäàòèâíûå ïðîöåññû ÷åðåç àêòèâàöèþ FoxO è óâåëè÷åíèå ýêñïðåññèè ñóïåðîêñèääèñìóòàçû [76]. Ïî-âèäèìîìó, Klotho âîâëå÷åí â ïðîöåññû ýíäîòåëèàëüíîé èíòåãðàöèè è ôóíêöèè [77, 78].

73
Mirza MA, Hansen T, Johansson L et al. Relationship between circulating FGF-23 and total body atherosclerosis in the community. Nephrol Dial Transplant 2009; 24 (10): 3125– 3131
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  1. In-text reference with the coordinate start=29847
    Prefix
    Òàê, â ðÿäå äîñòàòî÷íî êðóïíûõ îáñåðâàöèîííûõ èññëåäîâàíèé ïðîäåìîíòðèðîâàíî, ÷òî ïîâûøåíèå FGF23 ñâÿçàíî ñ íàðóøåíèÿìè ýíäîòåëèÿ, âûðàæåííîñòüþ àòåðîñêëåðîçà, ãèïåðòðîôèåé ìèîêàðäà, ñîñóäèñòîé êàëüöèôèêàöèåé
    Exact
    [38, 71–75]
    Suffix
    . Öèðóëèðóþùàÿ ôîðìà Klotho îáëàäàåò ñïîñîáíîñòüþ ñíèæàòü îêñèäàòèâíûå ïðîöåññû ÷åðåç àêòèâàöèþ FoxO è óâåëè÷åíèå ýêñïðåññèè ñóïåðîêñèääèñìóòàçû [76]. Ïî-âèäèìîìó, Klotho âîâëå÷åí â ïðîöåññû ýíäîòåëèàëüíîé èíòåãðàöèè è ôóíêöèè [77, 78].

74
Yilmaz MI, Sonmez A, Saglam M et al. FGF-23 and vascular dysfunction in patients with stage 3 and 4 chronic kidney disease. Kidney Int 2010; 78 (7): 679–685
Total in-text references: 1
  1. In-text reference with the coordinate start=29847
    Prefix
    Òàê, â ðÿäå äîñòàòî÷íî êðóïíûõ îáñåðâàöèîííûõ èññëåäîâàíèé ïðîäåìîíòðèðîâàíî, ÷òî ïîâûøåíèå FGF23 ñâÿçàíî ñ íàðóøåíèÿìè ýíäîòåëèÿ, âûðàæåííîñòüþ àòåðîñêëåðîçà, ãèïåðòðîôèåé ìèîêàðäà, ñîñóäèñòîé êàëüöèôèêàöèåé
    Exact
    [38, 71–75]
    Suffix
    . Öèðóëèðóþùàÿ ôîðìà Klotho îáëàäàåò ñïîñîáíîñòüþ ñíèæàòü îêñèäàòèâíûå ïðîöåññû ÷åðåç àêòèâàöèþ FoxO è óâåëè÷åíèå ýêñïðåññèè ñóïåðîêñèääèñìóòàçû [76]. Ïî-âèäèìîìó, Klotho âîâëå÷åí â ïðîöåññû ýíäîòåëèàëüíîé èíòåãðàöèè è ôóíêöèè [77, 78].

75
Kirkpantur A, Balci M, Gurbuz CA et al. Serum fibroblast growth factor-23 (FGF-23) levels are independently associated with left ventricular mass and myocardial performance index in maintenance haemodialysis patients. Nephrol Dial Transplant 2011; 26 (4): 1346–1354
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  1. In-text reference with the coordinate start=29847
    Prefix
    Òàê, â ðÿäå äîñòàòî÷íî êðóïíûõ îáñåðâàöèîííûõ èññëåäîâàíèé ïðîäåìîíòðèðîâàíî, ÷òî ïîâûøåíèå FGF23 ñâÿçàíî ñ íàðóøåíèÿìè ýíäîòåëèÿ, âûðàæåííîñòüþ àòåðîñêëåðîçà, ãèïåðòðîôèåé ìèîêàðäà, ñîñóäèñòîé êàëüöèôèêàöèåé
    Exact
    [38, 71–75]
    Suffix
    . Öèðóëèðóþùàÿ ôîðìà Klotho îáëàäàåò ñïîñîáíîñòüþ ñíèæàòü îêñèäàòèâíûå ïðîöåññû ÷åðåç àêòèâàöèþ FoxO è óâåëè÷åíèå ýêñïðåññèè ñóïåðîêñèääèñìóòàçû [76]. Ïî-âèäèìîìó, Klotho âîâëå÷åí â ïðîöåññû ýíäîòåëèàëüíîé èíòåãðàöèè è ôóíêöèè [77, 78].

76
Kuro-o M. Klotho as a regulator of oxidative stress and senescence. Biol Chem 2008; 389 (3): 233–241
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  1. In-text reference with the coordinate start=30002
    Prefix
    Òàê, â ðÿäå äîñòàòî÷íî êðóïíûõ îáñåðâàöèîííûõ èññëåäîâàíèé ïðîäåìîíòðèðîâàíî, ÷òî ïîâûøåíèå FGF23 ñâÿçàíî ñ íàðóøåíèÿìè ýíäîòåëèÿ, âûðàæåííîñòüþ àòåðîñêëåðîçà, ãèïåðòðîôèåé ìèîêàðäà, ñîñóäèñòîé êàëüöèôèêàöèåé [38, 71–75]. Öèðóëèðóþùàÿ ôîðìà Klotho îáëàäàåò ñïîñîáíîñòüþ ñíèæàòü îêñèäàòèâíûå ïðîöåññû ÷åðåç àêòèâàöèþ FoxO è óâåëè÷åíèå ýêñïðåññèè ñóïåðîêñèääèñìóòàçû
    Exact
    [76]
    Suffix
    . Ïî-âèäèìîìó, Klotho âîâëå÷åí â ïðîöåññû ýíäîòåëèàëüíîé èíòåãðàöèè è ôóíêöèè [77, 78]. Òàêæå ïîêàçàíî, ÷òî Klotho ñâÿçûâàåòñÿ ñ ðåöåïòîðîì TGF-β 2-ãî òèïà, èíãèáèðóÿ åãî íèñõîäÿùèå ñèãíàëû è ñíèæàÿ ïðîÿâëåíèÿ èíòåðñòèöèàëüíîãî ôèáðîçà [79].

77
Kusaba T, Okigawa M, Matui A et al. Klotho is associated with VEGF receptor-2 and the transient receptor potential canonical-1 Ca2+ channel to maintain endothelial integrity. Proc Natl Acad Sci USA 2010; 107 (45): 19308–19313
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  1. In-text reference with the coordinate start=30086
    Prefix
    Öèðóëèðóþùàÿ ôîðìà Klotho îáëàäàåò ñïîñîáíîñòüþ ñíèæàòü îêñèäàòèâíûå ïðîöåññû ÷åðåç àêòèâàöèþ FoxO è óâåëè÷åíèå ýêñïðåññèè ñóïåðîêñèääèñìóòàçû [76]. Ïî-âèäèìîìó, Klotho âîâëå÷åí â ïðîöåññû ýíäîòåëèàëüíîé èíòåãðàöèè è ôóíêöèè
    Exact
    [77, 78]
    Suffix
    . Òàêæå ïîêàçàíî, ÷òî Klotho ñâÿçûâàåòñÿ ñ ðåöåïòîðîì TGF-β 2-ãî òèïà, èíãèáèðóÿ åãî íèñõîäÿùèå ñèãíàëû è ñíèæàÿ ïðîÿâëåíèÿ èíòåðñòèöèàëüíîãî ôèáðîçà [79]. Èíòåðåñíî, ÷òî Klotho îáíàðóæåí â ñèíîàòðèàëüíîì óçëå, à ñíèæåíèå ýêñïðåññèè ýòîãî áåëêà ñâÿçàíî ñ äèñôóíêöèåé ñèíîàòðèàëüíîãî óçëà è ïðåæäåâðåìåííîé ãèáåëüþ ýêñïåðèìåíòàëüíûõ æèâîòíûõ [80].

78
Nagai R, Saito Y, Ohyama Y et al. Endothelial dysfunction in the klotho mouse and downregulation of klotho gene expression in various animal models of vascular and metabolic diseases. Cell Mol Life Sci 2000; 57 (5): 738–746
Total in-text references: 1
  1. In-text reference with the coordinate start=30086
    Prefix
    Öèðóëèðóþùàÿ ôîðìà Klotho îáëàäàåò ñïîñîáíîñòüþ ñíèæàòü îêñèäàòèâíûå ïðîöåññû ÷åðåç àêòèâàöèþ FoxO è óâåëè÷åíèå ýêñïðåññèè ñóïåðîêñèääèñìóòàçû [76]. Ïî-âèäèìîìó, Klotho âîâëå÷åí â ïðîöåññû ýíäîòåëèàëüíîé èíòåãðàöèè è ôóíêöèè
    Exact
    [77, 78]
    Suffix
    . Òàêæå ïîêàçàíî, ÷òî Klotho ñâÿçûâàåòñÿ ñ ðåöåïòîðîì TGF-β 2-ãî òèïà, èíãèáèðóÿ åãî íèñõîäÿùèå ñèãíàëû è ñíèæàÿ ïðîÿâëåíèÿ èíòåðñòèöèàëüíîãî ôèáðîçà [79]. Èíòåðåñíî, ÷òî Klotho îáíàðóæåí â ñèíîàòðèàëüíîì óçëå, à ñíèæåíèå ýêñïðåññèè ýòîãî áåëêà ñâÿçàíî ñ äèñôóíêöèåé ñèíîàòðèàëüíîãî óçëà è ïðåæäåâðåìåííîé ãèáåëüþ ýêñïåðèìåíòàëüíûõ æèâîòíûõ [80].

79
Doi S, Zou Y, Togao O et al. Klotho inhibits transforming growth factor-beta1 (TGF-beta1) signaling and suppresses renal fibrosis and cancer metastasis in mice. J Biol Chem 2011; 286 (10): 8655–8665
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  1. In-text reference with the coordinate start=30245
    Prefix
    Ïî-âèäèìîìó, Klotho âîâëå÷åí â ïðîöåññû ýíäîòåëèàëüíîé èíòåãðàöèè è ôóíêöèè [77, 78]. Òàêæå ïîêàçàíî, ÷òî Klotho ñâÿçûâàåòñÿ ñ ðåöåïòîðîì TGF-β 2-ãî òèïà, èíãèáèðóÿ åãî íèñõîäÿùèå ñèãíàëû è ñíèæàÿ ïðîÿâëåíèÿ èíòåðñòèöèàëüíîãî ôèáðîçà
    Exact
    [79]
    Suffix
    . Èíòåðåñíî, ÷òî Klotho îáíàðóæåí â ñèíîàòðèàëüíîì óçëå, à ñíèæåíèå ýêñïðåññèè ýòîãî áåëêà ñâÿçàíî ñ äèñôóíêöèåé ñèíîàòðèàëüíîãî óçëà è ïðåæäåâðåìåííîé ãèáåëüþ ýêñïåðèìåíòàëüíûõ æèâîòíûõ [80]. Ýòè äàííûå ìîãóò èìåòü ïðÿìîå îòíîøåíèå ê êëèíè÷åñêèì ñèòóàöèÿì, ïîñêîëüêó óðîâåíü Klotho îò÷åòëèâî ñíèæåí ó áîëüíûõ ñ ÕÁÏ [41].

80
Takeshita K, Fujimori T, Kurotaki Y et al. Sinoatrial node dysfunction and early unexpected death of mice with a defect of klotho gene expression. Circulation 2004; 109 (14): 1776– 1782
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  1. In-text reference with the coordinate start=30438
    Prefix
    Òàêæå ïîêàçàíî, ÷òî Klotho ñâÿçûâàåòñÿ ñ ðåöåïòîðîì TGF-β 2-ãî òèïà, èíãèáèðóÿ åãî íèñõîäÿùèå ñèãíàëû è ñíèæàÿ ïðîÿâëåíèÿ èíòåðñòèöèàëüíîãî ôèáðîçà [79]. Èíòåðåñíî, ÷òî Klotho îáíàðóæåí â ñèíîàòðèàëüíîì óçëå, à ñíèæåíèå ýêñïðåññèè ýòîãî áåëêà ñâÿçàíî ñ äèñôóíêöèåé ñèíîàòðèàëüíîãî óçëà è ïðåæäåâðåìåííîé ãèáåëüþ ýêñïåðèìåíòàëüíûõ æèâîòíûõ
    Exact
    [80]
    Suffix
    . Ýòè äàííûå ìîãóò èìåòü ïðÿìîå îòíîøåíèå ê êëèíè÷åñêèì ñèòóàöèÿì, ïîñêîëüêó óðîâåíü Klotho îò÷åòëèâî ñíèæåí ó áîëüíûõ ñ ÕÁÏ [41]. Îñíîâíîé ïðîáëåìîé â îöåíêå çíà÷åíèÿ Klotho äëÿ êëèíè÷åñêîé ïðàêòèêè îñòàåòñÿ îòñóòñòâèå ïðîñòûõ è íàäåæíûõ ìåòîäîâ åãî äåòåêöèè.

81
Maschio G, Tessitore N, D’Angelo A et al. Early dietary phosphorus restriction and calcium supplementation in the prevention of renal osteodystrophy. Am J Clin Nutr 1980; 33 (7): 1546–1554
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    Prefix
    Ïðè ýòîì, èíòåñòèíàëüíàÿ íàãðóçêà Ð èìååò ïðèíöèïèàëüíîå çíà÷åíèå, ïîýòîìó, íåóäèâèòåëüíî, ÷òî öåëûé ðÿä ðàííèõ èññëåäîâàíèé (çàäîëãî äî îòêðûòèÿ FGF23) ïðîäåìîíñòðèðîâàëè âûñîêóþ ýôôåêòèâíîñòü ñíèæåíèÿ ïîòðåáëåíèÿ Ð â îòíîøåíèè ïðîãðåññèðîâàíèÿ ÂÃÏÒ
    Exact
    [81, 82]
    Suffix
    . Ñîâðåìåííûå ïðåäñòàâëåíèÿ ïîçâîëÿþò áîëåå òî÷íî ðàññòàâèòü àêöåíòû â îòíîøåíèè ïðèìåíåíèÿ íèçêîôîñôàòíîé äèåòû, à ïðè åå íåäîñòàòî÷íîñòè ïðèìåíåíèå ôîñôàòñâÿçûâàþùèõ àãåíòîâ (ÔÑÀ). Òàê, î÷åâèäíî, ÷òî òàêàÿ ñòðàòåãèÿ äîëæíà ñòàòü îñíîâíûì èíñòðóìåíòîì â ïðîôèëàêòèêå ìèíåðàëüíûõ è êîñòíûõ íàðóøåíèé ó áîëüíûõ ñ ÕÁÏ.

82
Alfrey AC: Effect of dietary phosphate restriction on renal function and deterioration. Am J Clin Nutr 1988; 47 (1): 153–156 Ïîñòóïèëà â ðåäàêöèþ 27.10.2011 ã. Ïðèíÿòà â ïå÷àòü 18.11.2011 ã.
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    Prefix
    Ïðè ýòîì, èíòåñòèíàëüíàÿ íàãðóçêà Ð èìååò ïðèíöèïèàëüíîå çíà÷åíèå, ïîýòîìó, íåóäèâèòåëüíî, ÷òî öåëûé ðÿä ðàííèõ èññëåäîâàíèé (çàäîëãî äî îòêðûòèÿ FGF23) ïðîäåìîíñòðèðîâàëè âûñîêóþ ýôôåêòèâíîñòü ñíèæåíèÿ ïîòðåáëåíèÿ Ð â îòíîøåíèè ïðîãðåññèðîâàíèÿ ÂÃÏÒ
    Exact
    [81, 82]
    Suffix
    . Ñîâðåìåííûå ïðåäñòàâëåíèÿ ïîçâîëÿþò áîëåå òî÷íî ðàññòàâèòü àêöåíòû â îòíîøåíèè ïðèìåíåíèÿ íèçêîôîñôàòíîé äèåòû, à ïðè åå íåäîñòàòî÷íîñòè ïðèìåíåíèå ôîñôàòñâÿçûâàþùèõ àãåíòîâ (ÔÑÀ). Òàê, î÷åâèäíî, ÷òî òàêàÿ ñòðàòåãèÿ äîëæíà ñòàòü îñíîâíûì èíñòðóìåíòîì â ïðîôèëàêòèêå ìèíåðàëüíûõ è êîñòíûõ íàðóøåíèé ó áîëüíûõ ñ ÕÁÏ.