Inhibition of Renal Fibrosis and Glomerular Injury by Sacubitril/Valsartan, a Combination Angiotensin Receptor Blocker and Neprilysin Inhibitor, in a Salt-Sensitive Hypertensive Model Using Angiotensin 1 Receptor Knockout Mice: The Contribution of Non-Angiotensin Blocking Effects to Renal Protection

Rei Otsu,Ryuichi Morishita,Kanako May Brule,Hideo Shimizu,Kana Shibata,Yoshiaki Taniyama,Hiromi Rakugi,Jun Muratsu,Fumihiro Sanada,Tatsuya Fujikawa

doi:10.2174/1874220301805010108

Abstract

Introduction: “Aldosterone breakthrough,” which is observed in patients receiving long term treatment with angiotensin blockade, is strongly associated with the increased risk of a declining glomerular filtration rate through the profibrotic actions of aldosterone. Sacubitril/valsartan is a newly created combination medicine (the angiotensin receptor blocker valsartan and the neprilysin-inhibitor sacubitril). Therefore, sacubitril/valsartan should have additional organ-protective actions besides the angiotensin blockade. Methods: In this study, we examined the renal protective effect of sacubitril/valsartan in a salt-sensitive hypertension model using angiotensin II type 1a receptor (AT1aR) knockout mice. An oral administration of 1% NaCl solution with sacubitril/valsartan (30 or 60 mg/kg/day) or valsartan (15 or 30 mg/kg/day) alone beginning 7 days before administration of aldosterone was examined in an aldosterone infusion AT1R knockout mouse model as an aldosterone breakthrough model. Results / Conclusion: A significant decrease in Blood Pressure (BP) was observed in the sacubitril/valsartan group compared to the valsartan group under low and high doses. In addition, the pathological analysis of the kidney for glomerular fibrosis by Sirius red staining and for injury by PAS staining demonstrated significant reductions accompanied by a significant reduction in TGF-β in the sacubitril/valsartan group compared to the valsartan group. Overall, sacubitril/valsartan, which has the dual actions of the AT1R blockade and neprilysin inhibition, may have additional clinical values for the treatment of hypertensive patients with aldosterone breakthrough.

Highlights

Angiotensin (Ang) II type 1 Receptor (AT1R) Blockers (ARBs) have been widely used for the treatment of1874-2203/18 2018 Bentham OpenInhibition of Renal Fibrosis and Glomerular Injury by Sacubitril/ValsartanOpen Medicine Journal, 2018, Volume 5 109 hypertension and hypertension-related cardiovascular end-organ damage [1]
In this study, we demonstrated the inhibition of renal fibrosis and glomerular injury by Sac/Val, independent from the Ang II blockade
We compared the effects of valsartan and Sac/Val on the mouse model of salt-sensitive hypertension using angiotensin II type 1a receptor (AT1aR)-KO mice

Summary

Introduction

Angiotensin (Ang) II type 1 Receptor (AT1R) Blockers (ARBs) have been widely used for the treatment of1874-2203/18 2018 Bentham OpenInhibition of Renal Fibrosis and Glomerular Injury by Sacubitril/ValsartanOpen Medicine Journal, 2018, Volume 5 109 hypertension and hypertension-related cardiovascular end-organ damage [1]. In terms of its impact on global mortality and morbidity in a heart failure (PARADIGM-HF) trial, Sac/Val significantly reduced cardiovascular and all-cause mortality, as well as Heart Failure (HF) hospitalization, in patients with HF with reduced Ejection Fraction (HFrEF) compared with the Angiotensin-Converting Enzyme Inhibitor (ACEI) enalapril [4]. Based on these clinical trials, in patients with HF, Sac/Val seems to be superior for ACEI/ARB. To examine the effects of Sac/Val in the aldosterone breakthrough model, we employed a renal fibrosis model induced by aldosterone and 1% NaCl treatment in AT1aR-KO mice [5, 6]

Methods

Results

Discussion

Conclusion