PPARγ Expression and Function in Mesangial Cells: Implication for Renal Disease
Dominant negative mutations which inactivate the peroxisome proliferator-activated receptor gamma (PPARγ) nuclear receptor in man are associated with severe insulin resistance, diabetes and hypertension (Barroso I et al. Nature, 1999;402:880-883). Using RNase protection assay, Western blot analysis and immunostaining of cultured primary rat mesangial cells, we identified the presence of PPARγ message and protein. Electrophoretic mobility of a labeled PPARγ response element (PPRE) was retarded in the presence of mesangial cell nuclear extract, suggesting that PPARγ is functional in these cells. Addition of unlabelled PPRE efficiently competed away the PPARγ-PPRE protein complex, confirming specificity of binding of the PPARγ to the PPRE. PPARγ ligands, rosiglitazone (10 μM) and troglitazone (10 μM), both completely inhibited platelet derived growth factor (PDGF)-induced DNA synthesis measured as bromodeoxyuridine (BrdU) incorporation (p<0.05). When administered in anti-diabetic doses to streptozotocin-induced diabetic rats, troglitazone substantially normalized albumin excretion at 4 months (from 687.1 to 137.6 μg urinary albumin/mg creatinine, p<0.05), but did not affect hyperglycemia or hypertension in this model. These data suggest PPARγ activation may have direct effects to attenuate diabetic glomerular disease, possibly by inhibiting mesangial growth, which occurs early in the process of diabetic nephropathy. These results have therapeutic implications for diabetic glomerulosclerosis as well as proliferative mesangial diseases of the kidney.