Reduced renal α-Klotho expression in CKD patients and its effect on renal phosphate handling and vitamin D metabolism.
Reduced renal α-Klotho expression in CKD patients and its effect on renal phosphate handling and vitamin D metabolism.
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DOI：
10.1371/journal.pone.0086301
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Saito Y
中科院分区：
文献类型：
--
作者：
Sakan H;Nakatani K;Asai O;Imura A;Tanaka T;Yoshimoto S;Iwamoto N;Kurumatani N;Iwano M;Nabeshima Y;Konishi N;Saito Y
肾α-klotho(α-KL)是成纤维细胞生长因子23(FGF23)的共同受体，FGF23是一种磷酸激素，也是1，25(OH)2维生素D3(1，25VitD3)的调节因子。FGF23-α-KL信号的中断被认为是慢性肾脏疾病的早期标志，包括肾脏α-KL表达减少和血清FGF23的相对升高。然而，目前尚不清楚FGF23的升高是否与肾脏α-KL的丢失有关。我们检测了肾活检标本中α-KL的表达，并检测了慢性肾功能不全患者(n-α)血清和尿液中多种矿物质代谢指标以及可溶性 = -KL(SKL)水平。我们发现，尽管早、中期慢性肾脏病患者肾脏α-KL水平显著降低，血清FGF23水平显著升高，但血磷水平仍保持在正常范围内。多元回归分析显示，FGF23的升高与肾功能降低和血磷升高显著相关，但与肾脏α-KL的丢失无关。此外，尽管肾脏α-KL水平下降，但FGF23水平的增加增加了早期和中期慢性肾脏病患者的尿磷排泄分数，并降低了血清1，25VitD3水平，尽管在晚期慢性肾病患者中并非如此。血清sKL水平在慢性肾脏病病程中也显著下降，肾脏α-KL是sKL的重要独立决定因素。这些结果表明，在CKD的早期和中期，FGF23水平升高以补偿肾功能衰竭相关的磷酸盐滞留。这使得FGF23-α-KL信号和中性磷酸平衡得以维持，尽管α-KL减少。然而，在晚期慢性肾脏病中，肾脏α-KL进一步下降。这扰乱了FGF23信号，血清磷水平显著增加，刺激更多的FGF23分泌。我们的结果还表明，血清SKL浓度可能是肾脏α-KL表达水平的有用标志。
Renal α-Klotho (α-KL) plays a fundamental role as a co-receptor for fibroblast growth factor 23 (FGF23), a phosphaturic hormone and regulator of 1,25(OH)2 vitamin D3 (1,25VitD3). Disruption of FGF23-α-KL signaling is thought to be an early hallmark of chronic kidney disease (CKD) involving reduced renal α-KL expression and a reciprocal rise in serum FGF23. It remains unclear, however, whether the rise in FGF23 is related to the loss of renal α-KL. We evaluated α-KL expression in renal biopsy samples and measured levels of several parameters of mineral metabolism, as well as soluble α-KL (sKL), in serum and urinary samples from CKD patients (n = 236). We found that although renal α-KL levels were significantly reduced and serum FGF23 levels were significantly elevated in early and intermediate CKD, serum phosphate levels remained within the normal range. Multiple regression analysis showed that the increases in FGF23 were significantly associated with reduced renal function and elevated serum phosphate, but were not associated with loss of renal α-KL. Moreover, despite falling renal α-KL levels, the increase in FGF23 enhanced urinary fractional excretion of phosphate and reduced serum 1,25VitD3 levels in early and intermediate CKD, though not in advanced CKD. Serum sKL levels also fell significantly over the course of CKD, and renal α-KL was a significant independent determinant of sKL. These results demonstrate that FGF23 levels rise to compensate for renal failure-related phosphate retention in early and intermediate CKD. This enables FGF23-α-KL signaling and a neutral phosphate balance to be maintained despite the reduction in α-KL. In advanced CKD, however, renal α-KL declines further. This disrupts FGF23 signaling, and serum phosphate levels significantly increase, stimulating greater FGF23 secretion. Our results also suggest the serum sKL concentration may be a useful marker of renal α-KL expression levels.
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DOI：
10.1056/nejmoa0706130
发表时间：
2008-08-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
Gutiérrez OM;Mannstadt M;Isakova T;Rauh-Hain JA;Tamez H;Shah A;Smith K;Lee H;Thadhani R;Jüppner H;Wolf M
通讯作者：
Wolf M
DOI：
10.1006/bbrc.1997.8019
发表时间：
1998-01-26
影响因子：
3.1
作者：
Matsumura, Y;Aizawa, H;Nabeshima, Y
通讯作者：
Nabeshima, Y
影响因子：
3.5
作者：
Shiraki-Iida, T;Aizawa, H;Nabeshima, Y
通讯作者：
Nabeshima, Y
影响因子：
4.8
作者：
Kurosu, H;Ogawa, Y;Kuro-o, M
通讯作者：
Kuro-o, M
影响因子：
19.6
作者：
Nakatani, K;Fujii, H;Nose, M
通讯作者：
Nose, M