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

Abstract

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) worldwide. SGLT2 inhibitors are clinically effective in halting DKD progression. However, the underlying mechanisms remain unclear. The serum and kidneys of mice with DKD were analyzed using liquid chromatography with tandem mass spectrometry (LC–MS/MS)-based metabolomic and proteomic analyses. Three groups were established: placebo-treated littermate db/m mice, placebo-treated db/db mice and EMPA-treated db/db mice. Empagliflozin (EMPA) and placebo (10 mg/kg/d) were administered for 12 weeks. EMPA treatment decreased Cys-C and urinary albumin excretion compared with placebo by 78.60% and 57.12%, respectively (p < 0.001 in all cases). Renal glomerular area, interstitial fibrosis and glomerulosclerosis were decreased by 16.47%, 68.50% and 62.82%, respectively (p < 0.05 in all cases). Multi-omic analysis revealed that EMPA treatment altered the protein and metabolic profiles in the db/db group, including 32 renal proteins, 51 serum proteins, 94 renal metabolites and 37 serum metabolites. Five EMPA-related metabolic pathways were identified by integrating proteomic and metabolomic analyses, which are involved in renal purine metabolism; pyrimidine metabolism; tryptophan metabolism; nicotinate and nicotinamide metabolism, and glycine, serine and threonine metabolism in serum. In conclusion, this study demonstrated metabolic reprogramming in mice with DKD. EMPA treatment improved kidney function and morphology by regulating metabolic reprogramming, including regulation of renal reductive stress, alleviation of mitochondrial dysfunction and reduction in renal oxidative stress reaction.

Sodium-Glucose Cotransporter 2 Inhibitors: A Scoping Review of the Positive Implications on Cardiovascular and Renal Health and Dynamics for Clinical Practice

“…Therefore, the current eGFR limitation put by FDA (eGFR ≥45 ml/min/1.73 m 2 ) should be reconsidered [ 13 ] as cardiorenal benefits occur independently of glucosuria, based on findings observed in DAPA-HF trial in patients without diabetes [ 40 ]. Empagliflozin treatment in diabetic kidney disease mouse models was also conducted by Lu et al [ 64 ]. In the extraction of renal tissue, both proteomic and metabolomic analyses subsequently done demonstrated a positive alteration in renal tissue by preventing glomerular hypertrophy to the extent that the diabetic controlled had possessed after 12 weeks alongside a substantial decrease in interstitial fibrosis (at 62.8% compared to 68.5%).…”

Metabolomic profiling in kidney cells treated with a sodium glucose-cotransporter 2 inhibitor

“…The metabolomic study using the mouse renal cortical tissue has shown that differences in metabolism are evident in the ischemia/reperfusion + dapagliflozin group compared with the ischemia/reperfusion group [aminoacyl-tRNA biosynthesis, arginine and proline metabolism, valine, leucine and isoleucine biosynthesis, phenylalanine, tyrosine, and tryptophan biosynthesis, alanine, aspartate and glutamate metabolism, glycine, serine and threonine metabolism] 33 . Also, the significantly altered pathway of aminoacyl-tRNA biosynthesis, arginine and proline metabolism, bet-alanine metabolism has been identified in a diabetic mouse model after SGLT2 intervention 34 .…”

“…[aminoacyl-tRNA biosynthesis, arginine and proline metabolism, valine, leucine and isoleucine biosynthesis, phenylalanine, tyrosine, and tryptophan biosynthesis, alanine, aspartate and glutamate metabolism, glycine, serine and threonine metabolism] 33 . Also, the significantly altered pathway of aminoacyl-tRNA biosynthesis, arginine and proline metabolism, bet-alanine metabolism has been identified in a diabetic mouse model after SGLT2 intervention 34 . The renal arginine metabolism mainly occurs in proximal tubular epithelial cells 35 , and the previous study has shown that exposure to albumin can enhance arginine metabolism in these cells 36 .…”

Integrated gas chromatography‐mass spectrometry and ultra‐high‐performance liquid chromatography‐mass spectrometry renal metabolomics and lipidomics deciphered the metabolic regulation mechanism of Gushudan on kidney‐yang‐deficiency‐syndrome rats

“…Glycine, serine, and threonine metabolism is a branch of amino acid metabolism, and its disorder has been confirmed in chronic kidney disease [23]. Glycine, serine, and threonine metabolism improve the renal morphology and function of diabetic nephropathy mice by inhibiting the activity of SOD‐glucose co‐transporter 2, so as to reduce the renal damage caused by oxidative stress [24].…”