Neutral endopeptidase inhibitors blunt kidney fibrosis by reducing myofibroblast formation

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, in vivo , 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 AT1-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...

Source: Clinical Science - January 7, 2019 Category: Biomedical Science Authors: Bijkerk, R., Aleksinskaya, M. A., Duijs, J. M., Veth, J., Husen, B., Reiche, D., Prehn, C., Adamski, J., Rabelink, T. J., De Mey, J. G. R., van Zonneveld, A. J. Tags: PublishAheadOfPrint Source Type: research