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Dapagliflozin Ameliorates Diabetic Kidney Disease via Upregulating Crry and Alleviating Complement Over-activation in

Dong-Yuan Chang1,2,3, Xiao-Qian Li1,2,3, Min Chen1,2,3

  • 1Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.

Frontiers in Pharmacology
|October 29, 2021
PubMed

Insights

Sodium-glucose cotransporter 2 (SGLT2) inhibitors like dapagliflozin reduce kidney damage in diabetic kidney disease by decreasing complement system over-activation. This occurs through upregulating complement regulator Crry, linked to reduced HIF-1α accumulation.

Area of Science:

  • Nephrology
  • Immunology
  • Pharmacology

Background:

  • Diabetic kidney disease (DKD) involves detrimental complement system over-activation.
  • Sodium-glucose cotransporter 2 (SGLT2) inhibitors offer renal protection in DKD, partly via anti-inflammatory effects.
  • The role of SGLT2 inhibitors in modulating complement pathways in DKD requires further elucidation.

Purpose of the Study:

  • To investigate the impact of SGLT2 inhibitors on complement system over-activation in a mouse model of DKD.
  • To explore the underlying mechanisms, including the role of complement receptor type 1-related protein y (Crry) and HIF-1α.

Main Methods:

  • Utilized a db/db mouse model of DKD treated with dapagliflozin or vehicle.
  • Assessed renal pathological parameters, C3b, and membrane attack complex (MAC) deposition.
  • Cultured mouse proximal tubular epithelial cells (MPTECs) under high glucose, with dapagliflozin and DMOG treatment to study Crry and HIF-1α expression.

Main Results:

  • Dapagliflozin treatment significantly reduced urinary albumin and attenuated C3b and MAC deposition in db/db mice.
  • SGLT2 inhibition upregulated Crry expression, a key complement inhibitor.
  • Dapagliflozin's protective effect on Crry was linked to suppressed HIF-1α accumulation, which was reversed by DMOG-induced HIF-1α stabilization.

Conclusions:

  • Dapagliflozin attenuates complement over-activation in diabetic kidney disease by upregulating Crry expression.
  • This mechanism is associated with the suppression of HIF-1α accumulation in renal tubular cells.
  • SGLT2 inhibitors represent a promising therapeutic strategy for DKD by targeting the complement system.
Keywords:
complement over-activationcomplement receptor type 1-related protein y (Crry)dapagliflozindiabetic kidney diseasehypoxia inducible factor-1α (HIF-1 α)sodium glucose co-transport-2 (SGLT2) inhibitors

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