Cardiac and Renal Protective Effects of Irbesartan via Peroxisome Proliferator‐Activated Receptorγ–Hepatocyte Growth Factor Pathway Independent of Angiotensin II Type 1a Receptor Blockade in Mouse Model of Salt‐Sensitive Hypertension

BACKGROUND: “Aldosterone breakthrough” observed in patients receiving long‐term treatment with angiotensin blockade is strongly associated with increased risk of left ventricular hypertrophy, poor exercise capacity, refractory proteinuria, and declining glomerular filtration rate through the profibrotic actions of aldosterone. To overcome aldosterone breakthrough, we examined the additional organ‐protective actions of irbesartan, because irbesartan is an angiotensin II type 1 receptor (AT1R) blocker (ARB) with peroxisome proliferator‐activated receptor (PPAR)γ agonistic effects, which mediate organ‐protective effects independent of AT1R blockade. In this study, we examined the organ‐protective effects of irbesartan in a salt‐sensitive hypertension model using AT1aR knockout mice. METHODS AND RESULTS: Aldosterone and 1% NaCl treatment resulted in a significant increase in severe cardiac and renal fibrosis. Irbesartan, but not losartan, significantly reduced renal fibrosis, glomerular injury through inhibition of macrophage infiltration, epithelial–mesenchymal transition, and oxidative stress. Similarly, cardiac fibrosis and myocyte hypertrophy were decreased by irbesartan, but not losartan, treatment, associated with a significant reduction in oxidative stress. Importantly, anti–hepatocyte growth factor (HGF) neutralizing antibody and a PPARγ antagonist (GW9662) attenuated these organ‐protective effects of irbesartan. HGF protein level was increased by irbesartan, especially in the kidney and heart, while GW9662 treatment inhibited the increase in HGF level. CONCLUSIONS: In this study, we showed that irbesartan, which has not only AT1aR‐blocking effects, but also PPARγ agonistic effects accompanied by HGF expression, inhibited organ damage by aldosterone and salt treatment. Second‐generation ARBs such as irbesartan, which has the dual actions of AT1R blockade and PPARγ activation, may have clinical value for the treatment of hypertensive patients with aldosterone breakthrough.