Telmisartan Exerts Renoprotective Actions via Peroxisome Proliferator-Activated Receptor-γ/Hepatocyte Growth Factor Pathway Independent of Angiotensin II Type 1 Receptor Blockade

摘要

Angiotensin (Ang) II type 1 receptor blockers have demonstrated beneficial effects beyond blood pressure control in the treatment of chronic kidney disease. There is clinical evidence that telmisartan is more effective than losartan in reducing proteinuria in hypertensive patients with diabetic nephropathy, because it is a partial agonist of peroxisome-proliferator activated receptor-γ (PPARγ), as well as an Ang II type 1 receptor blocker (AMADEO Study [A comparison of telMisartan versus losArtan in hypertensive type 2 DiabEtic patients with Overt nephropathy]). In this study, we examined the role of PPARγ activation in the renal protective actions of telmisartan using Ang II type 1 receptor–deficient mice. Renal injury was induced in Ang II type 1 receptor–deficient mice by producing unilateral ureteral obstruction, which exhibited severe renal interstitial fibrosis and inflammation. In these mice, telmisartan prevented hydronephrosis induced by unilateral ureteral obstruction more strongly than did losartan. Importantly, the prevention of renal atrophy and fibrosis by telmisartan was significantly attenuated by GW9662, a PPARγ antagonist. Interestingly, the downstream effector of PPARγ activation by telmisartan is hepatocyte growth factor (HGF), a well-known antifibrotic factor, because renal HGF expression was significantly increased by telmisartan, and a neutralizing antibody against HGF diminished the renal protective action of telmisartan. These beneficial changes by telmisartan were associated with a decrease in the expression of transforming growth factor-β1 and other proinflammatory and profibrotic cytokine genes through PPARγ/HGF activation. Our findings provide evidence of organ protective actions of telmisartan through the PPARγ/HGF pathway, independent of Ang II type 1 receptor blockade. Further development of the next generation of Ang II type 1 receptor blockers with added organ protective actions, such as PPARγ activation, might provide new beneficial drugs to treat renal and cardiovascular diseases.