741 CARDIAC AND RENAL PROTECTIVE EFFECTS OF HEPATOCYTE GROWTH FACTOR (HGF), INDUCED BY IRBESARTAN IN MOUSE MODEL OF SALT-SENSITIVE HYPERTENSION

Abstract

Background: Irbesartan and telmisartan are Angiotensin (Ang) II type 1 receptor (AT1R) blockers (ARBs) with perioxisome-proliferator activated receptorγ (PPARγ) agonistic effects, which mediate organ protective effects independent of their AT1R blockade. Irbesaratan has especially strong cardiac and renal protective effects. Telmisartan reduces renal fibrosis and inflammation by inducing hepatocyte growth factor (HGF) expression, independently of AT1aR blockade in unilateral ureteral obstruction (UUO) models created in AT1aR knockout mice (AT1aR-KO). Here we test whether or not irbesartan exerts organ protective effects in mouse models of salt sensitive hypertension. Methods and Results: Aldosterone (0.15 μg/h) was subcutaneously infused into AT1aR-KO mice, using osmotic mini pumps and 1% NaCl were dissolved in drinking water for 4 weeks. Severe cardiac and renal fibrosis plus glomerular injury were confirmed. Irbesartan significantly reduces renal and cardiac fibrosis, glomerular injury, aortic oxidative stress and hypertrophy of the cardiac fiber. The phosphorylation of ERK and EGFR are also reduced by irbesartan treatment. On the other hand, when a neutralizing antibody against HGF and a PPARγ antagonist (GW9662) are added to irbesartan, these organ protective effects of irbesartan were not observed. Irbesartan also inactivates ERK and EGFR in cultured mesangial cells Conclusions: Irbesartan reduced organ injury in mouse models of salt sensitive hypertension, which is mediated by salt and aldosterone treatment. These effects were mediated via the PPARγ/HGF/EGFR pathway independently of its AT1R blocking effects.