SGLT2 inhibitors improve kidney function and morphology by regulating renal metabolic reprogramming in mice with...

Area of Science:

• Nephrology
• Metabolomics
• Proteomics

Background:

• Diabetic kidney disease (DKD) is a major cause of end-stage renal disease (ESRD).
• SGLT2 inhibitors show clinical efficacy in slowing DKD progression.
• Mechanisms underlying SGLT2 inhibitor action in DKD are not fully understood.

Purpose of the Study:

• To investigate the molecular mechanisms of Empagliflozin (EMPA) in treating diabetic kidney disease (DKD).
• To analyze metabolic and proteomic changes in the kidneys and serum of DKD mice treated with EMPA.

Main Methods:

• Liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based metabolomic and proteomic analyses were performed on serum and kidney samples.
• DKD was induced in db/db mice, with treatment groups including placebo and Empagliflozin (EMPA).
• Comparative analysis was conducted between placebo-treated db/m mice, placebo-treated db/db mice, and EMPA-treated db/db mice.

Main Results:

• EMPA treatment significantly reduced Cys-C and urinary albumin excretion.
• EMPA decreased renal pathological changes, including glomerular area, interstitial fibrosis, and glomerulosclerosis.
• Multi-omic analysis identified alterations in 32 renal proteins, 51 serum proteins, 94 renal metabolites, and 37 serum metabolites following EMPA treatment.
• Five EMPA-related metabolic pathways were identified, including purine and pyrimidine metabolism, tryptophan metabolism, nicotinate and nicotinamide metabolism, and glycine, serine, and threonine metabolism.

Conclusions:

• DKD is characterized by significant metabolic reprogramming.
• EMPA treatment effectively improves kidney function and morphology in DKD mice.
• EMPA exerts its therapeutic effects by regulating metabolic reprogramming, reducing renal reductive and oxidative stress, and alleviating mitochondrial dysfunction.