Negative growth effects of ciglitazone on kidney interstitial fibroblasts: role of PPAR-gamma.

Ciglitazone and other thiazolidinedione compounds are peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands and improve renal function in diabetic nephropathy independent of blood glucose control. Because interstitial fibroblasts and glomerular mesangial cells are important cell types affected in diabetic nephropathy, the major aim of the present study was to examine the effect of ciglitazone on apoptosis and growth of renal interstitial fibroblasts (NRKs) and glomerular mesangial cells (MMCs). The effect of ciglitazone on apoptosis and cell growth of cultured NRKs and MMCs was done using DNA fragmentation and MTS cell-growth assays, respectively. The potential role of PPAR-gamma in these two cell types was examined by reporter gene analysis. Ciglitazone induced caspase-dependent apoptosis of both NRKs and MMCs and caused a significant decrease in cell growth. Other PPAR-gamma ligands also mimicked this effect. Interestingly, ciglitazone did not activate the PPRE-TK-CAT (peroxisome proliferator regulatory element, a thymidine kinase promoter and a chloramphenicol acetyltransferase gene) when transfected into NRKs, suggesting that ciglitazone does not activate the endogenous PPAR-gamma system in NRKs. On the other hand, ciglitazone activated the endogenous PPAR-gamma in MMCs. Apoptotic and negative growth effects of ciglitazone, in NRKs, are not mediated through PPAR-gamma. The thiazolidinediones have important cellular effects on renal interstitial fibroblasts and glomerular mesangial cells that may be therapeutically useful in non-diabetic renal disease.