EFFECTS OF EMPAGLIFLOZIN ON SALT-SENSITIVE HYPERTENSION AND RENAL INFLAMMATION IN RAT

Abstract

Objective: Renal inflammation may have a role in salt-sensitive hypertension. Although sodium-glucose cotransporter-2 (SGLT2) inhibitors were reported to exert blood pressure lowering in type 2 diabetes mellitus, whether they have a role in non-diabetic kidney diseases is not clear. This study was undertaken to investigate whether salt-sensitive hypertension and its accompanying renal inflammation are ameliorated by SGLT2 inhibition.

Design and method: The animal model of salt-sensitive hypertension was established by salt loading in uninephrectomized rats. Male Sprague-Dawley rats were randomly divided into 3 groups: sham controls (SC, n = 4), uninephrectomized controls (UC, n = 4), and empagliflozin-treated rats (ET, n = 5). All rats were fed a rodent diet with 8% NaCl throughout the study period. Empagliflozin (20 mg/kg/d) was orally administered for 3 weeks after uninephrectomized rats were stabilized over 2 weeks. Systolic blood pressures (SBPs) were weekly measured, and kidneys were harvested for qPCR at the end of animal experiment.

Results: At baseline, SBPs were 122 ± 4, 127 ± 1, and 125 ± 3 mmHg in SC, UC, and ET, respectively. At the end of animal experiment, SBP in UC was higher than that in SC (167 ± 4 vs. 137 ± 6 mmHg, P < 0.01). However, ET had a lower SBP (146 ± 3 mmHg) compared with UC (P < 0.05). As expected, urinary glucose excretion was remarkable in ET (2.61 ± 0.59 mmol/d/100 g BW versus 0 in controls). Whereas natriuresis was not different between groups, urinary excretion of osmoles in ET (29.8 ± 3.6 mmol/d/100 g BW, P < 0.01) was higher than that in SC (20.6 ± 2.3 mmol/d/100 g BW) or UC (19.3 ± 1.4 mmol/d/100 g BW). Compared with SC, the mRNA expression level of IL-1β (268 ± 91%, P < 0.05), RANTES (167 ± 20%, P < 0.05), and gp91phox (300 ± 36%, P < 0.05) were increased in UC but ameliorated in ET (IL-1β, 159 ± 29%; RANTES, 87 ± 34%; gp91phox, 142 ± 74%, all P < 0.05).

Conclusions: Empagliflozin was effective in controlling salt-sensitive hypertension induced by renal mass reduction, via glycosuria-driven osmotic diuresis rather than natriuresis. The upregulation of renal inflammation in salt-sensitive hypertension may be relieved by empagliflozin treatment.