Angiotensin–neprilysin inhibition confers renoprotection in rats with diabetes and hypertension by limiting podocyte injury

Abstract

Objectives: Combined angiotensin receptor--neprilysin inhibition (ARNI) reduces glomerulosclerosis better than single angiotensin receptor blockade (ARB) in diabetic, hypertensive rats. The renoprotective mechanism remains unknown, but may depend on superior blood pressure control, improved renal hemodynamics, suppressed renal inflammation or prevention of podocyte loss. Methods: To address this, TGR(mREN2)27 rats (a model of angiotensin II-dependent hypertension) were made diabetic for 12 weeks and treated with vehicle (n = 10), valsartan (ARB; n = 7) or sacubitril/valsartan (ARNI; n = 8) for the final 3 weeks. Arterial pressure was measured via radiotelemetry. Results: Sacubitril/valsartan lowered mean arterial pressure by −50 ± 4 mmHg and valsartan by −43 ± 4 mmHg (P = 0.3). Both treatments lowered albuminuria, but only sacubitril/valsartan maintained high urinary atrial natriuretic peptide, improved glycemic control and protected podocyte integrity, reflected by increased nephrin expression and suppression of transient receptor potential canonical 6 and regulator of calcineurin 1. This resulted in markedly reduced glomerulosclerosis (P < 0.05 vs. control and valsartan). Despite higher effective renal plasma flow and glomerular filtration rates, sacubitril/valsartan did neither improve filtration fraction nor renal immune cell infiltration. Conclusion: Sacubitril/valsartan offers drug-class-specific renoprotection in a preclinical model of diabetes and hypertension. Renoprotection is unrelated to antihypertensive efficacy, renal hemodynamics or inflammation, but may be related to protective effects of natriuretic peptides on podocyte integrity.

Dual Angiotensin Receptor and Neprilysin Inhibitor Ameliorates Portal Hypertension in Portal Hypertensive Rats

“…In early stages of diabetic nephropathy, Habibi et al [34] showed that LCZ696 was superior to valsartan in reducing proteinuria, renal ultrastructure, and tubular injury in a murine model. Furthermore, a recent study demonstrated that the renoprotection effect of LCZ696 was attributed by limiting podocyte injury [35]. In the present study, we found that LCZ696 and valsartan treatments did not affect the plasma level of creatinine, an indicator of renal injury.…”

Protective Renal Effects of Atrial Natriuretic Peptide: Where Are We Now?

“…Considering the beneficial effects of ANP in the kidney and the deleterious effects of the RAS, the use of a combined inhibition that favors the protective actions of ANP and blocks the harmful effects of Ang II represents an interesting approach to evaluate. In this way, the dual inhibition of the angiotensin receptor AT1 and neprilysin (called ARNI) is a novel therapy that combines a neprilysin inhibitor (sacubitril) that enhances the action of ANP, and a selective antagonist of the AT1 receptor (valsartan) that counteracts the increase in Ang II induced by sacubitril while avoiding the incidence of cough and angioedema caused by ACE inhibitors ( Uijl et al, 2020 ). ARNIs are currently indicated for patients with heart failure (HF) with reduced ejection fraction, where they have shown benefits in terms of morbidity and mortality ( McMurray et al, 2014 ).…”

“…Another study demonstrated that treatment with ARNI was associated with increased ANP levels and significant protection against kidney damage in SHRSP rats compared to valsartan alone ( Rubattu et al, 2018 ). Other studies that used an experimental model of angiotensin II-dependent hypertensive diabetic rats [TGR (mREN2) 27 rats] demonstrated that chronic treatment with sacubitril/valsartan was associated with increased in urinary ANP levels, reduced albuminuria, and less development of segmental glomerulosclerosis compared to valsartan monotherapy ( Roksnoer, 2016 ; Uijl et al, 2020 ). This renoprotective effect of ANP would be independent of its antihypertensive efficacy and could be related to a reduction in renal inflammation.…”

The Effect of Sacubitril/Valsartan Treatment on Cardiac and Renal Functions of a Patient With Cardiorenal Syndrome Type 4 and Stage 5 CKD After More Than Three Years of Follow-Up

“…As cardiac function improved, renal perfusion enhanced, followed by an increased GFR. In addition, compared with traditional RASI, ARNI significantly reduced proteinuria, improved renal ultrastructure, and decreased biomarkers of the renal tubulointerstitial lesion ( 30 , 31 ), which is independent of blood pressure reduction. The acting mechanisms are considered as inhibition of inflammation and oxidative stress, as well as drug-specific protection of podocyte integrity ( 30 – 32 ).…”