Neutral endopeptidase inhibitors blunt kidney fibrosis by reducing myofibroblast formation

• Published in: Clinical science (1979) Vol. 133; no. 2; pp. 239 - 252
• Main Authors: Bijkerk, Roel, Aleksinskaya, Marina A, Duijs, Jacques Mgj, Veth, Jennifer, Husen, Bettina, Reiche, Dania, Prehn, Cornelia, Adamski, Jerzy, Rabelink, Ton J, De Mey, Jo G R, van Zonneveld, Anton Jan
• Format: Journal Article
• Language: English
• Published: England 31.01.2019
• Subjects: transcriptomics; cGMP; metabolomics; myofibroblast; kidney fibrosis; neutral endopeptidase inhibition
• ISSN: 0143-5221; 1470-8736
• DOI: 10.1042/CS20180882

Kidney fibrosis is the common pathophysiological mechanism in end-stage-renal-disease characterized by excessive accumulation of myofibroblast-derived extracellular matrix. Natriuretic peptides have been demonstrated to have cGMP-dependent anti-fibrotic properties likely due to interference with pro-fibrotic TGF-β signaling. However, , natriuretic peptides are rapidly degraded by neutral endopeptidases (NEP). In a unilateral urether obstruction (UUO) mouse model for kidney fibrosis we assessed the anti-fibrotic effects of SOL1, an orally-active compound that inhibits NEP and endothelin-converting enzyme (ECE). Mice (n=10 per group) subjected to UUO were treated for 1 week with either solvent, NEP-/ECE-inhibitor SOL1 (two doses), reference NEP-inhibitor candoxatril or the AT -receptor antagonist losartan. While NEP-inhibitors had no significant effect on blood pressure, they did increase urinary cGMP levels as well as Endothelin-1 (ET-1) levels. Immunohistochemical staining revealed a marked decrease in renal collagen (~55% reduction,P<0.05) and α-smooth muscle actin (α-SMA; ~40% reduction,P<0.05). Moreover, the number of α-SMA positive cells in the kidneys of SOL1-treated groups inversely correlated with cGMP levels consistent with a NEP-dependent anti-fibrotic effect. To dissect the molecular mechanisms associated with the anti-fibrotic effects of NEP inhibition, we performed a "Deep SAGE" transcriptome and targeted metabolomics analysis of total kidneys of all treatment groups. Pathway analyses linked increased cGMP and ET-1 levels with decreased nuclear receptor signaling (PPAR and LXR/RXR signaling) and actin cytoskeleton organization. Taken together, although our transcriptome and metabolome data indicate metabolic dysregulation, our data supports the therapeutic potential of neutral endopeptidase inhibition in the treatment of kidney fibrosis via cGMP elevation and reduced myofibroblast formation.