Expression and function of peroxisome proliferator-activated receptor-gamma in mesangial cells

P:eroxisome proliferator-activated receptor-gamma (PPARgamma) is a novel nuclear receptor, which enhances insulin-mediated glucose uptake. Ligands to PPARgamma are currently used as therapy for type II diabetes. Using Western blot analysis, RNase protection assay, and immunostaining, we identified the presence of PPARgamma message and protein in cultured primary rat mesangial cells. Electrophoretic mobility of a labeled PPARgamma response element (PPRE) was retarded in the presence of mesangial cell nuclear extract, suggesting that PPARgamma is functional in these cells. The addition of unlabeled PPRE efficiently competed away the PPARgamma-PPRE protein complex, confirming specificity of binding of the PPARgamma to the PPRE. PPARgamma ligands rosiglitazone (1 to 10 micromol/L) and troglitazone (1 to 10 micromol/L) inhibited platelet-derived growth factor-induced DNA synthesis, measured as bromodeoxyuridine incorporation (P<0.01). This inhibition was dose dependent. When administered in antidiabetic doses to streptozotocin-induced diabetic rats, troglitazone substantially normalized albumin excretion at 3 months (from 687.1 to 137.6 microgram urinary albumin/mg creatinine, P:<0.05) but did not affect hyperglycemia or blood pressure in this model. This treatment also decreased glomerular plasminogen activator inhibitor-1 (PAI-1) expression. These data suggest that PPARgamma activation may directly attenuate diabetic glomerular disease, possibly by inhibiting mesangial growth, which occurs early in the process of diabetic nephropathy, or by inhibiting PAI-1 expression. PAI-1 inhibits the activation of plasmin and matrix metalloproteinase, which degrade extracellular matrix in the glomerulus. Excess glomerular PAI-1 allows the accumulation of extracellular matrix, leading to glomerulosclerosis. These results have therapeutic implications for diabetic nephropathy as well as for proliferative mesangial diseases of the kidney.