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.