Possible renoprotective mechanisms of SGLT2 inhibitors

Abstract

Treatment with a sodium glucose cotransporter 2 (SGLT2) inhibitor in patients with chronic kidney disease reduces the renal risk independent of changes in blood glucose concentrations and blood pressure. However, the precise mechanism responsible for this SGLT2 inhibitor-induced renoprotective effect is unclear. We have previously shown that SGLT2 inhibitors induce antihypertensive effects with decreased sympathetic nerve activity, which is associated with transient natriuresis. Furthermore, treatment with an SGLT2 inhibitor improves renal ischemia by producing vascular endothelial growth factor-a in the renal tubules. Other studies have suggested that ketone body production, changes in glomerular hemodynamics, and intrarenal metabolic changes and a reduction in oxidative stress due to decreased tubulointerstitial glucose levels may also be involved in the renoprotective effects of SGLT2 inhibitors. In this review, we summarize the mechanism responsible for the SGLT2 inhibitor-induced renoprotective effects, including our recent hypothesis regarding an “aestivation-like response,” which is a biological defense response to starvation.

Do Sodium-Glucose Cotransporter 2 Inhibitors Decrease the Risk of Contrast-Associated Acute Kidney Injury in Patients with Type II Diabetes Mellitus?

“… 26 Other reported beneficial 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. 27 …”

Effect of Antidiabetic Drugs on Bone Health in Patients with Normal Renal Function and in Chronic Kidney Disease (CKD): Insight into Clinical Challenges in the Treatment of Type 2 Diabetes

“…Nephroprotective effects of SGLT2i rely on different mechanisms of action. Hemodynamic effects are exerted by a reduction in the intraglomerular pressure, as well as improvement in renal congestion mediated by movement of water from the interstitium to the urine [56,57]. Favorable effects of SGLT2i on the tubulointerstitial function were observed in animal models of kidney injury through a reduction in glucose concentration and oxidative stress in the proximal tubule [57].…”

“…Hemodynamic effects are exerted by a reduction in the intraglomerular pressure, as well as improvement in renal congestion mediated by movement of water from the interstitium to the urine [56,57]. Favorable effects of SGLT2i on the tubulointerstitial function were observed in animal models of kidney injury through a reduction in glucose concentration and oxidative stress in the proximal tubule [57]. Weight loss, reduction in serum glucose and insulin levels, and the natriuretic action of SGLT2i were linked in a rat model of obesity and hypertension with the anti-hypertensive effects of these drugs [57].…”

“…Favorable effects of SGLT2i on the tubulointerstitial function were observed in animal models of kidney injury through a reduction in glucose concentration and oxidative stress in the proximal tubule [57]. Weight loss, reduction in serum glucose and insulin levels, and the natriuretic action of SGLT2i were linked in a rat model of obesity and hypertension with the anti-hypertensive effects of these drugs [57]. Finally, a reduction in acute kidney injury was observed in mouse and rat models in association with an increased tubular expression of vascular endothelial growth factor, reduced energy expenditure in the proximal tubule, and amelioration of tubular oxygenation [56,57].…”

It’s Time for New Insights into Renovascular Hypertension at the Molecular Level

“…We are at a time when standard antihypertensive drugs, including ACE inhibitors and angiotensin receptor blockers (ARBs), have been complemented by SGLT2 inhibitors, which also contribute to indirect blood pressure reduction [5] [6].…”