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

Lu, Yong-Ping1,2; Zhang, Ze-Yu2; Wu, Hong-Wei2,3; Fang, Li-Jing4; Hu, Bo2; Tang, Chun1; Zhang, Yi-Qing1; Yin, Lianghong2; Tang, Dong-E1; Zheng, Zhi-Hua3; Zhu, Ting1; Dai, Yong3

2022-09-14

10.1186/s12967-022-03629-8

JOURNAL OF TRANSLATIONAL MEDICINE   Impact Factor & Quartile

1479-5876

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.

SCI

English

Corresponding

National Natural Science Foundation of China[8210032527] ; GuangDong Basic and Applied Basic Research Foundation[2020A1515111209] ; Young Innovative Talents Project of General Colleges and Universities in Guangdong Province[2018KQNCX010] ; Postdoctoral Fund the Seventh Affiliated Hospital, Sun Yat-sen University[ZSQYRSFPD0030] ; General program of China Postdoctoral Science Foundation[2021M703749]

Research & Experimental Medicine

Medicine, Research & Experimental

WOS:000853907500001

BMC

Web of Science

1.Sun Yat Sen Univ, Affiliated Hosp 7, Ctr Kidney & Urol, Dept Nephrol, Shenzhen, Peoples R China
2.Jinan Univ, Affiliated Hosp 1, Dept Nephrol, Guangzhou, Peoples R China
3.Jinan Univ, Southern Univ Sci & Technol, Guangdong Prov Engn Res Ctr Autoimmune Dis Precis, Affiliated Hosp 1,Shenzhen Peoples Hosp,Clin Med, Shenzhen 518020, Peoples R China
4.Guangzhou First Peoples Hosp, Dept Nephrol, Guangzhou, Peoples R China

Lu, Yong-Ping,Zhang, Ze-Yu,Wu, Hong-Wei,et al. SGLT2 inhibitors improve kidney function and morphology by regulating renal metabolic reprogramming in mice with diabetic kidney disease[J]. JOURNAL OF TRANSLATIONAL MEDICINE,2022,20(1).

Lu, Yong-Ping.,Zhang, Ze-Yu.,Wu, Hong-Wei.,Fang, Li-Jing.,Hu, Bo.,...&Dai, Yong.(2022).SGLT2 inhibitors improve kidney function and morphology by regulating renal metabolic reprogramming in mice with diabetic kidney disease.JOURNAL OF TRANSLATIONAL MEDICINE,20(1).

Lu, Yong-Ping,et al."SGLT2 inhibitors improve kidney function and morphology by regulating renal metabolic reprogramming in mice with diabetic kidney disease".JOURNAL OF TRANSLATIONAL MEDICINE 20.1(2022).