Background: Our laboratory has shown that troglitazone, a thiazolidinedione and peroxisomal proliferator activated receptor gamma (PPAR-gamma) agonist, prevents mesangial expansion and glomerulosclerosis in diabetic rats. We investigated and compared the action of two PPAR agonists at the level of the mesangial cell.
Methods: Rat mesangial cells were grown in medium containing 5 mmol/L glucose, 30 mmol/L glucose, or 5 mmol/L glucose plus 25 mmol/L mannitol. The cultures were either left untreated, treated with 10 micromol/L troglitazone (PPAR-gamma), or 100 micromol/L clofibrate (PPAR-alpha). The following parameters were used to assess mesangial cell responses: detection of PPAR-gamma and -alpha mRNA, the degree of PPAR-gamma and -alpha activation, spread cell area, total protein production, and laminin and type I collagen production.
Results: Reverse transcription-polymerase chain reaction (RT-PCR) showed the presence of PPAR-gamma and -alpha mRNA in rat mesangial cells. PPAR-gamma and -alpha proteins are active in mesangial cells and the extent of activation is affected by different glycemic conditions. Troglitazone and clofibrate treatment corrected in part the increase in spread cell area seen in mesangial cells in hyperglycemic conditions. However, neither agonist corrected the increase in total protein production induced by hyperglycemia. Treatment with troglitazone resulted in a significant, specific decrease in type I collagen along with a slight decrease in laminin production in both medium conditions. Clofibrate had no effect on laminin synthesis in either medium condition but did decrease type I collagen synthesis in cells grown in hyperglycemic conditions.
Conclusion: PPAR-alpha and -gamma mRNA signaling pathways are in place and active in mesangial cells. Both agonists affect the phenotypic behavior of mesangial cells and ameliorate changes resulting from hyperglycemia. The data indicate that the correction of mesangial cell phenotype by troglitazone may influence production/deposition of a pathological fibrotic connective tissue matrix (that is, type I collagen) by these cells.