Rosuvastatin protects against podocyte apoptosis in vitro
Rosuvastatin protects against podocyte apoptosis in vitro
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DOI：
10.1093/ndt/gfn528
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发表时间：
2009-02-01
影响因子：
6.1
通讯作者：
Durvasula, Raghu V.
中科院分区：
文献类型：
--
作者：
Cormack-Aboud, Fionnuala C.;Brinkkoetter, Paul T.;Durvasula, Raghu V.
背景。临床研究表明，他汀类药物可以减少慢性肾病患者的蛋白尿并减缓肾功能的下降。鉴于大量文献将足细胞凋亡确定为蛋白尿和肾小球硬化病理生理进展的早期步骤，我们假设瑞舒伐他汀可保护足细胞免于凋亡。关于潜在的机制，我们的实验室已经证明细胞周期蛋白 p21 在足细胞中具有促生存作用，并且有文献显示他汀类药物可以上调其他肾细胞中的 p21。因此，我们质疑瑞舒伐他汀是否通过 p21 依赖性途径促进足细胞存活。方法。两种独立的细胞凋亡触发物，嘌呤霉素氨基核苷（PA）和阿霉素（ADR），用于诱导 p21 +/+ 和 p21 -/- 条件永生化小鼠足细胞的细胞凋亡，无论是否预先暴露于瑞舒伐他汀。通过两种方法测量细胞凋亡：Hoechst 33342 染色和荧光激活细胞分选 (FACS)。为了确定 p21 的作用，在接触瑞舒伐他汀后通过蛋白质印迹法测量 p21 水平，并将 p21 稳定转导到 p21 -/- 小鼠足细胞中。结果。 Rosuvastatin 可防止 ADR 和 PA 诱导的足细胞凋亡。此外，接触瑞舒伐他汀会增加体外足细胞中 p21 的水平。 ADR 诱导 p21 -/- 小鼠足细胞凋亡，但在缺乏 p21 的情况下看不到瑞舒伐他汀的保护作用。在 p21 -/- 足细胞中重建 p21 可恢复瑞舒伐他汀的促生存作用。结论。瑞舒伐他汀可促进受损足细胞的存活。瑞舒伐他汀通过 p21 依赖性抗凋亡途径发挥其保护作用。这些发现表明他汀类药物通过防止足细胞凋亡和随后的足细胞减少来减少蛋白尿。
Background. Clinical studies suggest that statins 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 rosuvastatin protects podocytes from undergoing apoptosis. Regarding a potential mechanism, our lab has shown that the cell cycle protein, p21, has a prosurvial role in podocytes and there is literature showing statins upregulate p21 in other renal cells. Therefore, we queried whether rosuvastatin is prosurvival in podocytes through a p21-dependent pathway.Methods. Two independent apoptotic triggers, puromycin aminonucleoside (PA) and adriamycin (ADR), were used to induce apoptosis in p21 +/+ and p21 -/- conditionally immortalized mouse podocytes with or without pre-exposure to rosuvastatin. Apoptosis was measured by two methods: Hoechst 33342 staining and fluorescence-activated cell sorting (FACS). To establish a role for p21, p21 levels were measured by western blotting following rosuvastatin exposure and p21 was stably transduced into p21 -/- mouse podocytes.Results. Rosuvastatin protects against ADR- and PA-induced apoptosis in podocytes. Further, exposure to rosuvastatin increases p21 levels in podocytes in vitro. ADR induces apoptosis in p21 -/- mouse podocytes, but rosuvastatin's protective effect is not seen in the absence of p21. Reconstituting p21 in p21 -/- podocytes restores rosuvastatin's prosurvival effect.Conclusion. Rosuvastatin is prosurvival in injured podocytes. Rosuvastatin exerts its protective effect through a p21-dependent antiapoptotic pathway. These findings suggest that statins decrease proteinuria by protecting against podocyte apoptosis and subsequent podocyte depopulation.