TY - JOUR T1 - Comparison of Direct Action of Thiazolidinediones and Glucocorticoids on Renal Podocytes: Protection from Injury and Molecular Effects JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.111.071654 SP - mol.111.071654 AU - Shipra Agrawal AU - Adam J Guess AU - Rainer Benndorf AU - William E Smoyer Y1 - 2011/06/02 UR - http://molpharm.aspetjournals.org/content/early/2011/06/02/mol.111.071654.abstract N2 - The FDA-approved thiazolidinediones, pioglitazone and rosiglitazone, are peroxisome proliferator-activated receptor γ (PPARγ) agonists developed to control serum glucose in diabetic patients. They have subsequently been found to reduce proteinuria and microalbuminuria in both diabetic nephropathy and non-diabetic 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 which may be critical to their protective effects. Rosiglitazone deactivated the mitogen-activated protein kinases (MAPKs), ERK1/2, p38MAPK and SAPK/JNK, while pioglitazone did not and dexamethasone deactivated to some extent. Similar to dexamethasone, both thiazolidinediones increased the glucocorticoid receptor phosphorylation, and this response to Rosi and possibly to Pio was PPARγ-dependent. Furthermore, both drugs mimicked or enhanced the effects of dexamethasone on glucocorticoid-responsive genes, in a PPARγ- and GR-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. ER -