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NDT Advance Access originally published online on September 27, 2008
Nephrology Dialysis Transplantation 2009 24(2):404-412; doi:10.1093/ndt/gfn528
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Rosuvastatin protects against podocyte apoptosis in vitro

Fionnuala C. Cormack-Aboud, Paul T. Brinkkoetter, Jeffrey W. Pippin, Stuart J. Shankland and Raghu V. Durvasula

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



  Abstract

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


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