Sodium-glucose cotransporter inhibitors and kidney fibrosis: review of the current evidence and related mechanisms.

Abstract

Sodium-glucose cotransporter inhibitors (SGLT2i) are a new class of anti-diabetic drugs that have beneficial cardiovascular and renal effects. These drugs decrease proximal tubular glucose reabsorption and decrease blood glucose levels as a main anti-diabetic action. Furthermore, SGLT2i decreases glomerular hyperfiltration by a tubuloglomerular feedback mechanism. However, the renal benefits of these agents are independent of glucose-lowering and hemodynamic factors, and SGLT2i also impacts the kidney structure including kidney fibrosis. Renal fibrosis is a common pathway and pathological marker of virtually every type of chronic kidney disease (CKD), and amelioration of renal fibrosis is of utmost importance to reduce the progression of CKD. Recent studies have shown that SGLT2i impact many cellular processes including inflammation, hypoxia, oxidative stress, metabolic functions, and renin-angiotensin system (RAS) which all are related with kidney fibrosis. Indeed, most but not all studies showed that renal fibrosis was ameliorated by SGLT2i through the reduction of inflammation, hypoxia, oxidative stress, and RAS activation. In addition, less known effects on SGLT2i on klotho expression, capillary rarefaction, signal transducer and activator of transcription signaling and peptidylprolyl cis/trans isomerase (Pin1) levels may partly explain the anti-fibrotic effects of SGLT2i in kidneys. It is important to remember that some studies have not shown any beneficial effects of SGLT2i on kidney fibrosis. Given this background, in the current review, we have summarized the studies and pathophysiologic aspects of SGL2 inhibition on renal fibrosis in various CKD models and tried to explain the potential reasons for contrasting findings.