Abstract

The U.S. Food and Drug Administration-approved thiazolidinediones pioglitazone and rosiglitazone are peroxisome proliferator-activated receptor-γ (PPARγ) agonists developed to control serum glucose in patients with diabetes. They have been found to reduce proteinuria and microalbuminuria in both diabetic nephropathy and nondiabetic glomerulosclerosis. We hypothesized that the renal protective effects of thiazolidinediones result, at least in part, from their direct action on podocytes, similar to glucocorticoids. Treatment with pioglitazone, rosiglitazone, or dexamethasone significantly protected podocytes against puromycin aminonucleoside-induced injury (designed to mimic nephrotic syndrome-related injury), as determined by both cell survival and actin cytoskeletal integrity. Furthermore, we compared the ability of these drugs to modulate key signaling pathways in podocytes that may be critical to their protective effects. Rosiglitazone deactivated the mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinases 1/2, p38 MAPK, and stress-activated protein kinase/c-Jun NH₂-terminal kinase, whereas pioglitazone did not, and dexamethasone deactivated to some extent. Similar to dexamethasone, both thiazolidinediones increased the glucocorticoid receptor phosphorylation, and this response to rosiglitazone and possibly to pioglitazone was PPARγ-dependent. Furthermore, both drugs mimicked or enhanced the effects of dexamethasone on glucocorticoid-responsive genes in a PPARγ- and glucocorticoid receptor-dependent manner. In addition, both thiazolidinediones mimicked dexamethasone-induced effects on calcineurin activity. In summary, thiazolidinediones are able to modulate the glucocorticoid pathway and exert direct protective effects on podocytes, similar to glucocorticoids. This suggests that thiazolidinediones may have potential clinical utility as either primary or adjunctive therapy for nephrotic syndrome or other diseases treated with glucocorticoids. These findings may also lend mechanistic insight into the well established but poorly understood renal protective effects of thiazolidinediones in diabetic nephropathy.