The combination of a neprilysin inhibitor (sacubitril) and angiotensin-II receptor blocker (valsartan) attenuates glomerular and tubular injury in the Zucker Obese rat

Abstract

ObjectiveDiabetic nephropathy (DN) is characterized by glomerular and tubulointerstitial injury, proteinuria and remodeling. Here we examined whether the combination of an inhibitor of neprilysin (sacubitril), a natriuretic peptide-degrading enzyme, and an angiotensin II type 1 receptor blocker (valsartan), suppresses renal injury in a pre-clinical model of early DN more effectively than valsartan monotherapy.MethodsSixty-four male Zucker Obese rats (ZO) at 16 weeks of age were distributed into 4 different groups: Group 1: saline control (ZOC); Group 2: sacubitril/valsartan (sac/val) (68 mg kg−1 day−1; ZOSV); and Group 3: valsartan (val) (31 mg kg−1 day−1; ZOV). Group 4 received hydralazine, an anti-hypertensive drug (30 mg kg−1 day−1, ZOH). Six Zucker Lean (ZL) rats received saline (Group 5) and served as lean controls (ZLC). Drugs were administered daily for 10 weeks by oral gavage.ResultsMean arterial pressure (MAP) increased in ZOC (+ 28%), but not in ZOSV (− 4.2%), ZOV (− 3.9%) or ZOH (− 3.7%), during the 10 week-study period. ZOC were mildly hyperglycemic, hyperinsulinemic and hypercholesterolemic. ZOC exhibited proteinuria, hyperfiltration, elevated renal resistivity index (RRI), glomerular mesangial expansion and podocyte foot process flattening and effacement, reduced nephrin and podocin expression, tubulointerstitial and periarterial fibrosis, increased NOX2, NOX4 and AT1R expression, glomerular and tubular nitroso-oxidative stress, with associated increases in urinary markers of tubular injury. None of the drugs reduced fasting glucose or HbA1c. Hypercholesterolemia was reduced in ZOSV (− 43%) and ZOV (− 34%) (p < 0.05), but not in ZOH (− 13%) (ZOSV > ZOV > ZOH). Proteinuria was ameliorated in ZOSV (− 47%; p < 0.05) and ZOV (− 30%; p > 0.05), but was exacerbated in ZOH (+ 28%; p > 0.05) (ZOSV > ZOV > ZOH). Compared to ZOC, hyperfiltration was improved in ZOSV (p < 0.05 vs ZOC), but not in ZOV or ZOH. None of the drugs improved RRI. Mesangial expansion was reduced by all 3 treatments (ZOV > ZOSV > ZOH). Importantly, sac/val was more effective in improving podocyte and tubular mitochondrial ultrastructure than val or hydralazine (ZOSV > ZOV > ZOH) and this was associated with increases in nephrin and podocin gene expression in ZOSV (p < 0.05), but not ZOV or ZOH. Periarterial and tubulointerstitial fibrosis and nitroso-oxidative stress were reduced in all 3 treatment groups to a similar extent. Of the eight urinary proximal tubule cell injury markers examined, five were elevated in ZOC (p < 0.05). Clusterin and KIM-1 were reduced in ZOSV (p < 0.05), clusterin alone was reduced in ZOV and no markers were reduced in ZOH (ZOSV > ZOV > ZOH).ConclusionsCompared to val monotherapy, sac/val was more effective in reducing proteinuria, renal ultrastructure and tubular injury in a clinically relevant animal model of early DN. More importantly, these renoprotective effects were independent of improvements in blood pressure, glycemia and nitroso-oxidative stress. These novel findings warrant future clinical investiga...

ARNi: A Novel Approach to Counteract Cardiovascular Diseases

“…Improvement in the prognosis of patients assigned to sacubitril/valsartan also remained consistent in the subgroup of prediabetic, undiagnosed diabetic, and diagnosed diabetic patients, who are at a higher risk of adverse CV outcomes [53]. This evidence agrees with previous preclinical data demonstrating the cardio- and nephroprotective effects of ARNi [54,55,56,57].…”

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

“…Emerging data showed that LCZ696 is more effective than valsartan therapy alone in delaying the progression of kidney disease via antiinflammation, antioxidant, and antifibrosis effects [33]. 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].…”

Angiotensin II receptor Neprilysin inhibitor (LCZ696) compared to Valsartan attenuates Hepatotoxicity in STZ-induced hyperglycemic rats

“…Valsartan (Tabuvan®) and LCZ696 (EntrestoTM) tablets were suspended in 0.5% carboxymethyl cellulose (CMC) and administered by oral gavage in a volume of 0.5 ml/100 g body weight of each animal. For both medications, dose selection was based on previous literature 24 . During the experimental phase, the control and STZ groups were administered similar volumes of 0.5% CMC as the vehicle.…”