Effects of empagliflozin on nondiabetic salt-sensitive hypertension in uninephrectomized rats

Abstract

Impaired pressure natriuresis (PN) underlies salt-sensitive hypertension, and renal inflammation and hypoxia-inducible factor-1 (HIF-1) have been implicated in the modulation of systemic hypertension. Although sodium-glucose cotransporter-2 (SGLT2) inhibitors were reported to lower blood pressure (BP) in type 2 diabetes mellitus, whether they have a role in nondiabetic hypertensive kidney diseases is unclear. The present study was undertaken to investigate whether nondiabetic salt-sensitive hypertension and accompanying renal inflammation are ameliorated by SGLT2 inhibition. Male Sprague-Dawley rats were randomly divided into three groups: sham controls (SCs), uninephrectomized controls (UCs), and empagliflozin-treated rats (ETs). All rats were fed a rodent diet with 8% NaCl throughout the study period. Empagliflozin was orally administered for 3 weeks after uninephrectomy. Systolic blood pressure was recorded weekly, and kidneys were harvested for immunoblotting, immunohistochemistry, and quantitative PCR analysis at the end of the animal experiment. Systolic BP was significantly decreased in ETs that were orally given empagliflozin for 3 weeks after uninephrectomy. Although ETs did not show any increase in weekly measured urine sodium, the right-shifted PN relationship in UCs was improved by empagliflozin treatment. The expression of HIF-1α was increased in the renal outer medulla of ETs. Consistent with this, HIF prolyl-hydroxylase-2 protein and mRNA were decreased in ETs. The abundance of CD3 and ED-1 immunostaining in UCs was reduced by empagliflozin treatment. The increased IL-1ß, gp91phox, and NOX4 mRNA levels in UCs were also reversed. Empagliflozin restored impaired PN in nondiabetic hypertensive kidney disease in association with increased renal medullary expression of HIF-1α and amelioration of renal inflammation.

Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium–glucose cotransporter 2 inhibitors

“…Canagliflozin increases the expression, phosphorylation and activation of AMPK; although similar effects have been reported for empagliflozin and dapagliflozin, the evidence is less certain . Both canagliflozin and empagliflozin have been shown to upregulate SIRT1, and both empagliflozin and dapagliflozin induce the expression of HIF‐1α . Interestingly, in the renal tubules, there appears to be an inverse relationship between the activity of SGLT2 and the expression of both SIRT1 and HIF‐1α .…”

“…101,108,109,[147][148][149] Both canagliflozin and empagliflozin have been shown to upregulate SIRT1, 148,150 and both empagliflozin and dapagliflozin induce the expression of HIF-1 . 151,152 Interestingly, in the renal tubules, there appears to be an inverse relationship between the activity of SGLT2 and the expression of both SIRT1 and HIF-1 . 103,150,153…”

Role of Impaired Nutrient and Oxygen Deprivation Signaling and Deficient Autophagic Flux in Diabetic CKD Development: Implications for Understanding the Effects of Sodium-Glucose Cotransporter 2-Inhibitors

“…55,185,[196][197][198] Additionally, SGLT2 inhibitors may influence HIF-1a in a manner that favorably affects the course of CKD. 199,200 The hypothesis that SGLT2 inhibitors exert their effects to slow diabetic CKD progression primarily by modulating signaling through low energy-triggered enzymes and transcription factors (SIRT1 and hypoxia-inducible factors) and by stimulating autophagy is worthy of further study.…”

Sodium–Glucose Cotransporter 2 Inhibitors Work as a “Regulator” of Autophagic Activity in Overnutrition Diseases

“…SGLT2 inhibitors are reported to improve the imbalance of HIF-1α and HIF-2α. The overactivation of HIF-1α is improved via the decrease in serum glucose, AGEs, mTORC1 formation, and the increase of AMPK ( Bessho et al, 2019 ; Kim et al, 2019 ), and the downregulation of HIF-2α is improved via SIRT1 activation ( Chen et al, 2011 ; Chen et al, 2012 ) by the therapeutic effect of SGLT2 inhibitors. Thus, SGLT2 inhibitors improve the imbalance of HIF-1α and HIF-2α, ameliorate fibrosis and anemia, and contribute to the autophagy deficiency in DKD.…”