Xiao Houqin, Shi Wei, Liu Shuangxin, Wang Wenjian, Zhang Bin, Zhang Yong, Xu Lixia, Liang Xinling, Liang Yongzheng
Division of Nephrology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangdong, PR China.
Am J Nephrol. 2009;30(1):34-43. doi: 10.1159/000200769. Epub 2009 Feb 6.
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.
A rat model of podocyte apoptosis was created by a single intravenous injection of 100 mg x 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.
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.
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.
越来越多的证据表明，维生素D及其类似物可减少蛋白尿，并减缓慢性肾病患者肾功能的下降。鉴于有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，我们推测维生素D可保护足细胞免于凋亡。
通过单次静脉注射100mg·kg⁻¹嘌呤霉素氨基核苷（PAN）建立足细胞凋亡大鼠模型，并给予溶剂或1,25(OH)₂D₃治疗。分别评估蛋白尿、足细胞凋亡、nephrin蛋白和mRNA的表达、转化生长因子-β（TGF-β）/Smad和磷脂酰肌醇3激酶（PI3K）/Akt信号通路。
PAN诱导PAN肾病大鼠出现大量蛋白尿、血清肌酐升高和足细胞凋亡，这与nephrin的丢失、肾小球裂孔特异性黏附分子的减少以及p-Akt/Akt比值的降低有关。此外，PAN诱导足突回缩、nephrin重新分布以及TGF-β/Smad信号通路的激活。与PAN肾病大鼠相比，1,25(OH)₂D₃通过刺激Akt磷酸化和抑制TGF-β/Smad信号通路，显著预防了nephrin的丢失、足突回缩和足细胞凋亡。
1,25(OH)₂D₃减少了PAN肾病大鼠中PAN诱导的足细胞凋亡和nephrin的丢失。1,25(OH)₂D₃对足细胞的抗凋亡作用可能部分归因于PI3K/Akt生存通路的激活。
