Molecular Signaling Mediated by (Pro)Renin Receptor Blockade Leads to Attenuation of Cardiac Fibrosis in CKD-associated Heart Failure

Chronic kidney disease (CKD) is a major cardiovascular risk factor because of elevated tissue renin-angiotensin system activity in the heart. Although the (pro)renin receptor ((P)RR), specific receptor for renin and (pro)renin, is expressed in the cardiovascular system, its precise function in CKD heart has not yet been elucidated. We investigated the role of (P)RR and underlying molecular mechanism in CKD-associated heart failure using subtotal nephrectomy (STN, 5/6 kidney resection) mice and age-matched control mice treated with handle region peptide (HRP; a peptide which blocks (P)RR). STN was performed in 8-week-old male C57BL/6J mice. Eight weeks later, renal dysfunction was established, cardiac dysfunction and remodeling were apparent with hypertension. Mice were then assigned to three following groups; vehicle (saline), low-dose HRP (0.01 mg/kg/day), high-dose HRP (0.3 mg/kg/day) for 4 weeks. High-dose, but not low-dose, HRP treatment reversed left ventricular dilatation and significantly mitigated cardiac dysfunction with ameliorated hypertension compared to vehicle. The hearts of high-dose HRP treatment showed significant attenuation of fibrosis, macrophage infiltration and number of 8-hydroxy-2'-deoxyguanosine-positive cardiomyocyte. These phenotypes were accompanied by decreased expression of angiotensin II (ANGII), ANGII type 1 receptor, TGF-β1, TIMP1 and diminished phosphorylation of HSP27, ERK, p38 in hearts. HRP was not harmful to sham operated mice. In conclusion, our findings suggest (P)RR blockade is a useful therapeutic anti-fibrosis strategy against CKD-associated heart failure.