PPARy agonists inhibit TGF-beta-PKA signaling in glomerulosclerosis

Aim: To study the probable mechanisms of the anti-glomerulosclerosis effects induced by peroxisome proliferator-activated receptor gamma (PPARy) agonists in rat intraglomerular mesangial cells (MCs). Methods: Cells were transfected with the pTAL-PPRE-tk-Luc(+) plasmid and then treated with different concentrations of PPARy agonist, either troglitazone or telmisartan, for the indicated times. Promega luciferase assays were subsequently used for the detection of PPAR. activation. Protein expression levels were assessed by Western blot, and PepTag (R) assays were used for the non-radioactive detection of protein kinase A (PKA) activity. The deposition of alpha-smooth muscle actin (alpha-SMA) and p-cyclic AMP responsive element binding protein (pCREB) were analyzed by confocal laser scanning. Results: Both troglitazone and telmisartan remarkably inhibit the PKA activation and pCREB expression that is stimulated by TGF-beta. The PPARy agonists also inhibited alpha-SMA and collagen IV protein expression by blocking PKA activation. Conclusion: PPARy ligands effectively suppress the activation of MCs and the accumulation of collagen IV stimulated by TGF-beta in vitro. The renal protection provided by PPARy agonists is partly mediated via their blockade of TGF-beta/PKA signaling.