Dapagliflozin Ameliorates Diabetic Kidney Disease via Upregulating Crry and Alleviating Complement Over-activation in db/db Mice.

Dong-Yuan Chang,Xiao-Qian Li,Ming-Hui Zhao,Min Chen

doi:10.3389/fphar.2021.729334

Abstract

Sodium-glucose cotransporter 2(SGLT2) inhibitors show prominent renal protective effect in diabetic kidney disease (DKD), anti-inflammatory effect being one of its key mechanisms. Over-activation of the complement system, a crucial part of innate immunity, plays an important role in DKD. We aimed to investigate the effect of SGLT2 inhibitors on alleviating complement over-activation in DKD. Db/db mice were randomly divided into two groups, with 7 mice in each group treated with dapagliflozin and vehicle respectively, and 7 mice in m/m mice group. Laboratory and renal pathological parameters were evaluated. Mouse proximal tubular epithelial cells (MPTECs) were cultured and treated with high glucose. Dapagliflozin and dimethyloxallyl glycine (DMOG) were added as conditional treatment. Dapagliflozin-treated db/db mice showed significantly lower urinary albumin than vehicle-treated ones. Besides typical glomerular and tubulointerstitial injury, both C3b and membrane attack complex (MAC) depositions were significantly attenuated in dapagliflozin-treated db/db mice. The expression of complement receptor type 1-related protein y (Crry), a key complement regulator which inhibits complement over-activation, was significantly upregulated by dapagliflozin. Dapagliflozin-mediated Crry upregulation was associated with inhibition of HIF-1α accumulation under high glucose. When HIF-1α expression was stabilized by DMOG, the protective effect of dapagliflozin via upregulating Crry was blocked. In conclusion, dapagliflozin could attenuate complement over-activation in diabetic mice via upregulating Crry, which is associated with the suppression of HIF-1α accumulation in MPTECs.

Highlights

With the increasing prevalence of diabetes, diabetic kidney disease (DKD) has surpassed glomerulonephritis and become the leading cause of chronic kidney disease and end-stage renal disease (ESRD) (Zhang et al, 2016; Wang et al, 2017; Ma, 2018)
The current study found that the sodium-glucose cotransporter 2 (SGLT2) inhibitor alleviates complement over-activation by upregulating complement receptor type 1related protein y (Crry) expression via reducing Hypoxiainducible factor (HIF)-1α accumulation in renal proximal tubular cells in DKD
Increasing evidence demonstrated that the inflammatory process mediated mainly by innate immunity is among the central pathophysiology of DKD (Tang and Yiu, 2020)

Summary

Introduction

With the increasing prevalence of diabetes, diabetic kidney disease (DKD) has surpassed glomerulonephritis and become the leading cause of chronic kidney disease and end-stage renal disease (ESRD) (Zhang et al, 2016; Wang et al, 2017; Ma, 2018). The sodium-glucose cotransporter 2 (SGLT2) inhibitor is a novel anti-diabetic medication, targeting renal proximal tubules to reduce glucose reabsorption, resulting in increased urinary. SGLT2 inhibitors have already been recommended as the first-line medication for patients with chronic kidney diseases for the management of type 2 diabetes (Kidney Disease: Improving Global Outcomes Diabetes Work, 2020). Cumulating evidence suggests that, besides the anti-hyperglycemic effect, SGLT2 inhibitors have a remarkable anti-inflammatory role in DKD (Ashrafi Jigheh et al, 2019; Hasan et al, 2020; Pirklbauer et al, 2020)

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