Background. To elucidate the regulation of peroxisome proliferator- activated receptor γ (PPARγ) and its roles in mesangial cells, we examined the expression of PPARγ1 and effects of its ligands on cell phenotypes and angiotensin II-induced contractile response in cultured rat mesangial cells under a high (20 mmol/L) glucose condition. Methods. The effects of tumor necrosis factor α (TNFα), protein kinase C (PKC) activation, antisense DNA for PPARγ1, PPARγ ligands and PD98059 were examined in mesangial cells cultured in either 5 mmol/L or 20 mmol/L glucose. The expressions of PPARγ1 protein and α-smooth muscle actin (αSMA) as a marker of phenotype of cells were determined by Western blot. The expression of PPARγ1 mRNA was determined by a reverse transcription-polymerase chain reaction method. The reduction of cell surface area in response to angiotensin II was measured by microscope to determine cellular contraction. Results. PKC activation, TNFα, and 20 mmol/L glucose decreased PPARγ1 at both protein and mRNA levels, which was inhibited by PD98059, a specific inhibitor of mitogen-activated protein kinase (MAPK). Decreases of PPARγ1 protein and contractile response and an increase of αSMA occurred simultaneously in the cells treated with 20 mmol/L glucose after 5 days, which were attenuated to the normal levels by PPARγ ligands. The antisense DNA also induced the decrease of PPARγ1 protein, contractile dysfunction, and increase of αSMA. Conclusion. MAPK suppresses PPARγ1 at the transcriptional level, and the reduction of PPARγ1 in cultured rat mesangial cells under the high glucose condition induces phenotypic change and loss of contractile function. PPARγ ligands recover both reductions of PPARγ 1 protein and contractile response.
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