Rosuvastatin protects against podocyte apoptosis in vitro.
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.


CONCLUSIONS
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.
Cormack-Aboud
Fionnuala C
FC
Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, WA98195, USA.
Brinkkoetter
Paul T
PT
Pippin
Jeffrey W
JW
Shankland
Stuart J
SJ
Durvasula
Raghu V
RV
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity; D005464:Fluorobenzenes / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D050199:Podocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D011507:Proteinuria / Q000517:prevention & control; D011692:Puromycin Aminonucleoside / Q000633:toxicity; D011743:Pyrimidines / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*; D014161:Transduction, Genetic
D050759:Cyclin-Dependent Kinase Inhibitor p21; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D011994:Recombinant Proteins; D013449:Sulfonamides; D011692:Puromycin Aminonucleoside; D004317:Doxorubicin; D000068718:Rosuvastatin Calcium