Renocardiac protective effects of SGLT2 inhibitor combined with angiotensin receptor blocker in salt sensitive Dahl rats
Authors: Ito H , Dohi K , Zhe Y , Ali Y , Katayama K , Okamoto R , Ito M 
Published: October 2021

Abstract

Background
Kidney plays a central role in regulating salt-sensitivity of blood pressure (BP) to governs sodium excretion via several mechanisms including pressure natriuresis and the actions of renal sodium transporters.

Purpose
We clarified the effects of combination treatment of sodium-glucose cotransporter 2 (SGLT2) inhibitor and angiotensin receptor blocker (ARB) on BP and the pathogenesis of renocardiac injuries, and elucidated underlying molecular mechanisms involved in the regulation of renal sodium handling in the development of salt-sensitivity by comparing with each monotreatment in Dahl salt-sensitive (DSS) hypertensive rats.

Methods
DSS rats were treated orally for 8-weeks with normal salt diet (0.3% NaCl) (NS/Cont group), high salt diet (8% NaCl) (HS/Cont group), high salt diet with ipragliflozin (0.04%) (HS/Ipra group), high salt diet with losartan (0.05%) (HS/Los group), or high salt diet with combination of ipragliflozin and losartan (HS/Ipra+Los group).

Results
The combination group significantly reduced systolic BP compared with either high salt diet control group, losartan or ipragliflozin monotreatment groups (HS/Ipra+Los: 182.5±18.4mmHg vs HS/Cont: 227.7±26.1; HS/Ipra: 216.6±26.9; HS/Los: 208.6±21.6, at 8-weeks of treatment, P&lt;0.05, respectively) (Figure 1A). The slope of pressure-natriuresis curve was significantly increased in the HS/Ipra+Los group compared to that in the HS/Cont group (interaction P=0.024), HS/Ipra group (P=0.009), and HS/Los group (P=0.084) using the linear regression model (Figure 1B), which indicated that only the combination treatment of ipragliflozin and losartan improved salt-sensitivity. The combined treatment significantly improved creatinine clearance (HS/Ipra+Los: 3.3±0.9mL/min vs HS/Cont: 1.1±0.5; HS/Ipra: 1.7±0.6; HS/Los: 1.9±0.8, P&lt;0.05, respectively). The combination treatment also significantly ameliorated glomerulosclerosis, and improved cardiomyocyte hypertrophy and perivascular fibrosis (Figure 1C). Angiotensin II type 1 receptor (AT1R) protein expression level in the kidney was remarkably suppressed in the combination treatment group compared to the other high salt diet groups. The protein expression level of Na+/H+ exchanger isoform 3 (NHE3) and Na+-K+-Cl– cotransporter 2 (NKCC2), two of major sodium transports in the renal tubules, were significantly decreased with losartan monotreatment and combination treatment, but not with ipragliflozin monotreatment (Figure 2).

Conclusions
The dual inhibition of SGLT2 and AT1R effectively improved salt-sensitivity via reducing renal expression levels of the sodium transporters, which eventually lead to renocardiac protection. Thus, the combination treatment could be a novel and useful therapeutic strategy for treating salt-sensitive hypertension and renal injury in non-diabetic patients.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Grant-in-Aid for Scientific Research