1,25-Dihydroxyvitamin D3 Prevents Puromycin Aminonucleoside-Induced Apoptosis of Glomerular Podocytes by Activating the Phosphatidylinositol 3-Kinase/Akt-Signaling Pathway
1,25-Dihydroxyvitamin D3 Prevents Puromycin Aminonucleoside-Induced Apoptosis of Glomerular Podocytes by Activating the Phosphatidylinositol 3-Kinase/Akt-Signaling Pathway
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DOI：
10.1159/000200769
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发表时间：
2009-01-01
影响因子：
4.2
通讯作者：
Liang, Yongzheng
中科院分区：
文献类型：
--
作者：
Xiao, Houqin;Shi, Wei;Liang, Yongzheng
背景资料：越来越多的证据表明，维生素D及其类似物可以减少蛋白尿，减缓慢性肾脏疾病的肾功能下降。鉴于大量文献表明足细胞凋亡是蛋白尿和肾小球硬化病理生理进展的早期步骤，我们假设维生素D可保护足细胞免于凋亡。方法：采用单次静脉注射100 mg . kg（-1）嘌呤霉素氨基糖苷（PAN），分别用溶剂和1，25（OH）（2）D-3处理。分别检测蛋白尿、足细胞凋亡、nephrin蛋白和mRNA表达、TGF-β/Smad和磷脂酰肌醇3激酶（PI 3 K）/Akt信号通路。结果如下：PAN肾病大鼠出现大量蛋白尿、血清肌酐升高和足细胞凋亡，其机制与肾小球缝隙特异性粘附分子nephrin的丢失和p-Akt/Akt比值降低有关。此外，PAN还诱导足突收缩、nephrin重新分布和TGF-β/Smad信号通路的激活。与PAN肾病大鼠相比，1，25（OH）（2）D-3通过刺激Akt磷酸化和抑制TGF-β/Smad信号通路，显著抑制nephrin丢失、足突回缩和足细胞凋亡。结论：1，25（OH）（2）D-3可减少PAN肾病大鼠足细胞凋亡和nephrin的丢失。1，25（OH）（2）D-3对足细胞的抗凋亡作用可能部分归因于PI 3 K/Akt存活途径的激活。版权所有（C）2009 S. Karger AG，巴塞尔
Background: Accumulating evidence suggests that vitamin D and its analogs reduce proteinuria and slow the decline in kidney function in chronic kidney disease. Given a rich literature identifying podocyte apoptosis as an early step in the pathophysiological progression to proteinuria and glomerulosclerosis, we hypothesized that vitamin D protects podocytes from undergoing apoptosis. Methods: A rat model of podocyte apoptosis was created by a single intravenous injection of 100 mg . kg(-1) puromycin aminonucleoside (PAN) and received either solvent or 1,25(OH)(2)D-3 treatment. Proteinuria, podocyte apoptosis, the expression of nephrin protein and mRNA, TGF-beta/Smad and phosphatidylinositol 3-kinase (PI3K)/Akt-signaling pathway were evaluated, respectively. Results: PAN induced massive proteinuria, serum creatinine elevation and podocyte apoptosis in PAN nephropathy rats, which was associated with the loss of nephrin, an adhesion molecule specific for the glomerular slit and the reduced of p-Akt/Akt ratio. Moreover, PAN induced foot process retraction, redistribution of nephrin and the activation of TGF-beta/Smad-signaling pathway. Compared with PAN nephropathy rats, 1,25(OH)(2)D-3 significantly prevented loss of nephrin, foot process retraction and podocyte apoptosis by stimulating Akt phosphorylation and suppressing TGF-beta/Smad-signaling pathway. Conclusion: 1,25(OH)(2)D-3 reduced the PAN-induced podocyte apoptosis and loss of nephrin in PAN nephropathy rat. The anti-apoptotic effects of 1,25(OH)(2)D-3 on podocytes may be partly attributable to activation of a PI3K/Akt survival pathway. Copyright (C) 2009 S. Karger AG, Basel