NDT Advance Access published online on September 27, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn528
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Rosuvastatin protects against podocyte apoptosis in vitro
Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, WA98195, USA
Correspondence and offprint requests to: Raghu V. Durvasula, Division of Nephrology, University of Washington, Box 356521, BB-1265 HSB, 1959 NE Pacific Street, Seattle, WA 98195-6521. Tel: +206-542-2402; Fax: +206-685-8661; E-mail: rdrvsula{at}u.washington.edu
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Abstract |
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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.
Keywords: podocyte; apoptosis; p21; statins
Received for publication: 20. 5.08
Accepted in revised form: 29. 8.08