Hepatocyte Growth Factor Is a Downstream Effector that Mediates the Antifibrotic Action of Peroxisome Proliferator– Activated Receptor- Agonists

Peroxisome proliferator–activated receptor(PPAR) is a ligand-dependent transcription factor that plays an important role in the regulation of insulin sensitivity and lipid metabolism. Evidence shows that PPARagonists also ameliorate renal fibrotic lesions in both diabetic nephropathy and nondiabetic chronic kidney disease. However, little is known about the mechanism underlying their antifibrotic action. This study demonstrated that PPARagonists could exert their actions by inducing antifibrotic hepatocyte growth factor (HGF) expression. Incubation of mesangial cells with natural or synthetic PPARagonists 15-deoxy-prostaglandin J2 (15d-PGJ2) or troglitazone and ciglitazone suppressed TGF1–mediated -smooth muscle actin, fibronectin, and plasminogen activator inhibitor-1 expression. PPARagonists also induced HGF mRNA expression and protein secretion. Transfection studies revealed that 15d-PGJ2 stimulated HGF gene promoter activity, which was dependent on the presence of a novel peroxisome proliferator response element. Treatment of mesangial cells with 15d-PGJ2 induced the binding of PPARto the peroxisome proliferator response element in the HGF promoter region. PPARagonists also activated c-met receptor tyrosine phosphorylation, induced Smad transcriptional co-repressor TGinteracting factor expression, and blocked TGF/Smad-mediated gene transcription in mesangial cells. Furthermore, ablation of c-met receptor through the LoxP-Cre system in mesangial cells abolished the antifibrotic effect of 15d-PGJ2. PPARactivation also induced HGF expression in renal interstitial fibroblasts and repressed TGF1–mediated myofibroblast activation. Both HGF and 15d-PGJ2 attenuated Smad nuclear translocation in response to TGF1 stimulation in renal fibroblasts. Together, these findings suggest that HGF may act as a downstream effector that mediates the antifibrotic action of PPARagonists. J Am Soc Nephrol •: •••–•••, ••••. doi: 10.1681/ASN.2005030257