A sodium-glucose cotransporter 2 inhibitor attenuates renal capillary injury and fibrosis by a vascular endothelial growth factor–dependent pathway after renal injury in mice

Abstract

Multiple large clinical trials have shown that sodium-glucose cotransporter (SGLT) 2 inhibitors reduce the risk of renal events. However, the mechanism responsible for this outcome remains unknown. Here we investigated the effects of the SGLT2 inhibitor luseogliflozin on the development of renal fibrosis after renal ischemia/reperfusion injury in non-diabetic mice. Luseogliflozin significantly suppressed development of renal fibrosis, prevented peritubular capillary congestion/hemorrhage, attenuated CD31-positive cell loss, suppressed hypoxia, and increased vascular endothelial growth factor (VEGF)-A expression in the kidney after ischemia/reperfusion injury. Luseogliflozin failed to induce the above-mentioned protection in animals co-treated with sunitinib, a VEGF receptor inhibitor. Additionally, luseogliflozin reduced glucose uptake and increased VEGF-A expression in the kidneys of glucose transporter 2 (GLUT2)-downregulated mice following ischemia/reperfusion and in GLUT2-knock-down cells compared with those in normal controls. Withdrawal of glucose from cultured medium, to halt glucose uptake, remarkably increased VEGF-A expression and reversed the luseogliflozin-induced increase in VEGF-A expression in the proximal tubular cells. Thus, luseogliflozin prevented endothelial rarefaction and subsequent renal fibrosis after renal ischemia/reperfusion injury through a VEGF-dependent pathway induced by the dysfunction of proximal tubular glucose uptake in tubules with injury-induced GLUT2 downregulation.

Failure to confirm a sodium–glucose cotransporter 2 inhibitor‐induced hematopoietic effect in non‐diabetic rats with renal anemia

“…In the present study, hiPSC‐derived erythropoietin‐producing cells were treated with vehicle (2‐hydroxylpropyl‐β‐cyclodextrin; n = 5), 100 nmol/L luseogliflozin ( n = 4), 500 nmol/L luseogliflozin ( n = 4) or 50 µmol/L of FG‐4592 ( n = 3; Cayman, Ann Arbor, MI, USA). We previously showed that treatment with 100 nmol/L luseogliflozin sufficiently blocks SGLT2 in vitro . Previous work also showed that treatment with 50 µmol/L FG‐4592, a selective hypoxia‐inducible factor prolyl hydroxylase inhibitor, consistently increased the erythropoietin levels in the medium.…”

Evaluation of the effects of sodium–glucose co‐transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR‐Preserved Trial

“…Furthermore, SGLT2 inhibitors act to inhibit sodium reabsorption in the proximal renal tubules, in which the majority of renal sodium retention occurs; this action explains the marked reduction in plasma and/or interstitial volume and haemoconcentration seen in randomized controlled trials in type 2 diabetes . Moreover, SGLT2 inhibitors can attenuate renal inflammation and fibrosis . Additionally, the increased delivery of sodium to the macula densa that results from the inhibition of proximal tubular sodium reabsorption leads (through tubuloglomerular feedback) to a reduction in glomerular hyperfiltration, thereby ameliorating the major mechanism of glomerular injury in obesity and type 2 diabetes .…”

“…25,46 Moreover, SGLT2 inhibitors can attenuate renal inflammation and fibrosis. 17,47,48 Additionally, the increased delivery of sodium to the macula densa that results from the inhibition of proximal tubular sodium reabsorption leads (through tubuloglomerular feedback) to a reduction in glomerular hyperfiltration, thereby ameliorating the major mechanism of glomerular injury in obesity and type 2 diabetes. 33,34,49,50 Given the multiplicity of actions on cardiac, vascular and renal pathways that are relevant to the pathogenesis of HFpEF, it seems unlikely that a benefit of empagliflozin in this condition (if found in this trial) can be ascribed solely to its diuretic effects.…”

We Can Finally Stop Worrying About SGLT2 Inhibitors and Acute Kidney Injury

“…15 Other reported beneficial kidney effects include suppression of kidney fibrosis, decreased peritubular hemorrhage and fibrosis, reduced hypoxia, and increased renal vascular endothelial growth factor A expression in response to ischemia-reperfusion injury, which could preserve intrarenal perfusion and attenuate ischemic injury. 16 As reviewed elsewhere, the reduction in ischemia-reperfusion risk may have a variety of causes, which remain mainly hypothetical and merit further investigation. 17 With the benefit of hindsight, FDAERS reports of AKI may have reflected: (1) expected changes in eGFR on the basis of known hemodynamic effects and (2) higher risk for AKI in people with diabetes taking SGLT2 inhibitors on the basis of confounding AKI risk factors, including advanced age, greater proportion of men, and higher rates of renin-angiotensin-aldosterone system inhibitor and diuretic use.…”