Empagliflozin Ameliorates Free Fatty Acid Induced-Lipotoxicity in Renal Proximal Tubular Cells via the PPARγ/CD36 Pathway in Obese Mice

Int J Mol Sci. 2021 Nov 17;22(22):12408. doi: 10.3390/ijms222212408.

Abstract

High serum levels of free fatty acids (FFAs) could contribute to obesity-induced nephropathy. CD36, a class B scavenger receptor, is a major receptor mediating FFA uptake in renal proximal tubular cells. Empagliflozin, a new anti-diabetic agent, is a specific inhibitor of sodium-glucose co-transporter 2 channels presented on renal proximal tubular cells and inhibits glucose reabsorption. In addition, empagliflozin has shown renoprotective effects. However, the mechanism through which empagliflozin regulates CD36 expression and attenuates FFA-induced lipotoxicity remains unclear. Herein, we aimed to elucidate the crosstalk between empagliflozin and CD36 in FFA-induced renal injury. C57BL/6 mice fed a high-fat diet (HFD) and palmitic acid-treated HK-2 renal tubular cells were used for in vivo and in vitro assessments. Empagliflozin attenuated HFD-induced body weight gain, insulin resistance, and inflammation in mice. In HFD-fed mice, CD36 was upregulated in the tubular area of the kidney, whereas empagliflozin attenuated CD36 expression. Furthermore, empagliflozin downregulated the expression of peroxisome proliferator-activated receptor (PPAR)-γ. Treatment with a PPARγ inhibitor (GW9662) did not further decrease PPARγ expression, whereas a PPARγ antagonist reversed this effect; this suggested that empagliflozin may, at least partly, decrease CD36 by modulating PPARγ. In conclusion, empagliflozin can ameliorate FFA-induced renal tubular injury via the PPARγ/CD36 pathway.

Keywords: CD36; PPAR-gamma; SGLT2 inhibitor; empagliflozin; free fatty acid.

MeSH terms

  • Animals
  • Benzhydryl Compounds / administration & dosage*
  • CD36 Antigens / metabolism*
  • Cell Line, Transformed
  • Cell Survival / drug effects
  • Diet, High-Fat / adverse effects
  • Fatty Acids, Nonesterified / adverse effects*
  • Glucosides / administration & dosage*
  • Humans
  • Kidney Tubules, Proximal / cytology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • PPAR gamma / metabolism*
  • Palmitic Acid / pharmacology
  • Protective Agents / administration & dosage*
  • Renal Insufficiency / chemically induced*
  • Renal Insufficiency / drug therapy*
  • Renal Insufficiency / metabolism
  • Signal Transduction / drug effects*
  • Sodium-Glucose Transporter 2 Inhibitors / administration & dosage*
  • Treatment Outcome

Substances

  • Benzhydryl Compounds
  • CD36 Antigens
  • CD36 protein, human
  • Cd36 protein, mouse
  • Fatty Acids, Nonesterified
  • Glucosides
  • PPAR gamma
  • PPARG protein, human
  • Pparg protein, mouse
  • Protective Agents
  • Sodium-Glucose Transporter 2 Inhibitors
  • Palmitic Acid
  • empagliflozin