Neutral endopeptidase inhibitors SOL-1 and candoxatril counteract kidney fibrosis by reducing myofibroblast formation in mouse UUO model

Background Interstitial fibrosis is the common pathophysiological mechanism that leads to end organ failure of the both the heart and the kidney. Fibrosis is characterized by an excessive accumulation of myofibroblast-derived extracellular matrix. Peritubular capillary rarefaction precedes renal fibrosis and is secondary to the loss of capillary pericytes to the interstitium. Endothelial-derived C-type natriuretic peptide (CNP) has been demonstrated to have cGMP dependent anti-fibrotic properties most likely due to the interference with pro-fibrotic TGF-b signaling and may counteract the loss of the capillary pericytes. However, natriuretic peptides like CNP are rapidly degraded by neutral endopeptidase (NEP). In a unilateral urether obstruction (UUO) mouse model for kidney fibrosis we assessed the anti-fibrotic effects of Sol-1, a new orally-active compound (Solvay) that inhibits both neutral endopeptidase and endothelin.