Prevention against renal damage in rats with subtotal nephrectomy by sacubitril/valsartan (LCZ696), a dual‐acting angiotensin receptor‐neprilysin inhibitor

Abstract

Although patients with chronic kidney disease (CKD) are at increased risk for end‐stage renal disease and cardiovascular events, adequate drug therapies for preventing the deterioration of these conditions are still not established. This study was undertaken to evaluate a preventive effect of an angiotensin receptor‐neprilysin inhibitor sacubitril/valsartan (LCZ696), which is converted to sacubitril and valsartan in the body, against the progression of renal disease in rats with subtotal nephrectomy, an animal model of human CKD. Mean survival time after subtotal nephrectomy was about 100 days in Wistar rats with vehicle. LCZ696‐(30 mg/kg) and valsartan‐(15 mg/kg) prolonged the survival of these animals, and the effect of LCZ696 on survival was significantly greater than that of valsartan. Renoprotective effects of LCZ696 judged by serum creatinine and urinary protein excretions were larger than those of valsartan. Cardioprotective effects judged by cardiac left ventricular mass, fractional shortening, and fibrosis of LCZ696 and valsartan were not detected under the present condition. Thus, the renoprotective effect of LCZ696 was stronger than that of valsartan in rats with subtotal nephrectomy. This study provides the idea that, compared to valsartan, LCZ696 is more effective for the treatment of human CKD.

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

“…Therefore, some recent pre-clinical studies have begun to explore the mechanisms underlying the renoprotective effects of this drug combination. In this regard, two recent studies demonstrated superior renoprotection with sac/val compared to val monotherapy in rat models of severe CKD due to subtotal nephrectomy [ 56 , 57 ]. In the present study, we examined the effects of sac/val on glomerular, i.e ., filtration barrier injury, as well as, tubular remodeling and kidney fibrosis, along with associated changes in biochemical parameters in ZO rats, a translationally relevant model of early stage DN.…”

“…Herein, we observed that sac/val was more effective in lowering plasma total cholesterol compared to val or hydralazine. Since hypercholesterolemia in diabetes is usually associated with increased oxidized LDL and renal injury [ 57 , 61 ], it is possible that the improvement in plasma total cholesterol in ZOSV may have contributed, in part, to amelioration of kidney injury.…”

Vascular and Neural Complications in Type 2 Diabetic Rats: Improvement by Sacubitril/Valsartan Greater Than Valsartan Alone

“…Vasopeptidase inhibitors had shown promise as a treatment for chronic kidney disease in animal models, but as previously discussed, clinical development of this class of drugs was discontinued (35). Sacubitril/valsartan is now being studied as a potential treatment in a population of patients with chronic kidney disease as well as in animal models (34,36). This literature demonstrates that widespread studies are ongoing examining the potential benefits of angiotensin receptor-neprilysin inhibition in renal and cardiovascular diseases.…”

Repurposing of existing FDA approved drugs for Neprilysin inhibition: An in-silico study

“…The study report of the PARADIGM trial highlighted the role of NEP inhibitors in the population of heart failure with reduced ejection fraction [14] . In an in-vivo study of subtotal nephrectomy, the renoprotective effect of sacubitril/valsartan was found to be stronger as compared to valsartan alone [15] . According to the result of the U.K. HARP-III trial, the combination of sacubitril/valsartan is effective and is well-tolerated in the chronic kidney disease population [16] .…”