Ps-bpb02-1: possible differential effects of sacubitril/valsartan and valsartan against hypertension and cardiorenal injury in a mouse model of cardiorenal syndrome

Objective: Angiotensin receptor-neprilysin inhibitors (ARNI) are potential therapeutic candidates for the treatment of cardiorenal syndrome. Although evidence is accumulating on the therapeutic effects of ARNI for heart failure and hypertension, the effects of ARNI on kidney disease or cardiorenal syndrome are controversial. To address this issue, we investigated the organ-protective effect of ARNI on cardiorenal syndrome using the ANS [Ang II (A) + nephrectomy (N) + saline (S)] mice, which is the cardiorenal syndrome model. Design and method: C57BL/6 mice were divided into 5 groups: Control (sham operation) group, ANS (ANS + vehicle treatment) group, Val M [ANS + moderate dose of valsartan treatment (30 mg/kg/day)] group, ARNI [ANS + sacubitril/valsartan treatment (60 mg/kg/day)] group, and Val H [ANS + high dose of valsartan treatment (60 mg/kg/day)] group. Sacrifice was performed after 4 weeks, and various analyses were conducted. Results: ARNI, Val M, and Val H treatment groups attenuated the elevation of blood pressure in ANS mice; valsartan exerted its antihypertensive effect in a dose-dependent manner, and the antihypertensive effect of the ARNI group was intermediate between Val M and Val H groups. Regardless of the strength of the antihypertensive effect, the ARNI group was most effective in preventing the decrease in cardiac contraction and cardiac fibrosis in ANS mice. However, the ARNI group was insufficient to suppress urinary albumin excretion and renal fibrosis in ANS mice. Both valsartan groups suppressed urinary albumin excretion in ANS mice, as well as renal fibrosis and glomerular swelling. In addition, RNA sequencing analysis suggested that ARNI and valsartan may involve different molecular mechanisms in the kidney. Conclusions: The ARNI group showed better cardioprotective effects than both of valsartan treatment groups, but not sufficient kidney protection. These results of present study using a mouse model of cardiorenal syndrome suggested that the relationship between the antihypertensive effects and the organ protective effects of cardiorenal injury may be different between angiotensin II receptor blocker (ARB) and ARNI.