2. Academic Validation
  3. Dapagliflozin attenuates AKI to CKD transition in diabetes by activating SIRT3/PGC1-α signaling and alleviating aberrant metabolic reprogramming

Dapagliflozin attenuates AKI to CKD transition in diabetes by activating SIRT3/PGC1-α signaling and alleviating aberrant metabolic reprogramming

  • Biochim Biophys Acta Mol Basis Dis. 2024 Oct;1870(7):167433. doi: 10.1016/j.bbadis.2024.167433.
Huimin Li 1,  Yao Xia 2,  Hongchu Zha 2,  Yafei Zhang 2,  Lang Shi 3,  JiaYi Wang 4,  Hua Huang 2,  Ruchi Yue 1,  Bin Hu 5,  Jiefu Zhu 6,  Zhixia Song 7
Affiliations

Affiliations

  • 1 Department of Nephrology, The First Clinical Medical College of Three Gorges University, Center People's Hospital of Yichang, Yichang, Hubei 443000, China; Institute of Kidney Disease, Three Gorges University, Yichang, Hubei 443000, China; Department of Nephrology, Affiliated Renhe Hospital of China Three Gorges University, Yichang City 443001, Hubei Province, China.
  • 2 Department of Nephrology, The First Clinical Medical College of Three Gorges University, Center People's Hospital of Yichang, Yichang, Hubei 443000, China; Institute of Kidney Disease, Three Gorges University, Yichang, Hubei 443000, China.
  • 3 Institute of Kidney Disease, Three Gorges University, Yichang, Hubei 443000, China; Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China.
  • 4 Department of Anesthesiology, the Second Xiangya Hospital, Changsha, Hunan Province, China.
  • 5 Department of Nephrology, Affiliated Renhe Hospital of China Three Gorges University, Yichang City 443001, Hubei Province, China.
  • 6 Institute of Kidney Disease, Three Gorges University, Yichang, Hubei 443000, China; Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China.
  • 7 Department of Nephrology, the Longhua District People's Hospital of Shenzhen, Shenzhen, Guangdong 518000, China. Electronic address: songzhixia@ctgu.edu.cn.
PMID: 39067538 DOI: 10.1016/j.bbadis.2024.167433
Abstract

Background: Patients with diabetes are prone to acute kidney injury (AKI) with a high mortality rate, poor prognosis, and a higher risk of progression to chronic kidney disease than non-diabetic patients.

Methods: Streptozotocin (STZ)-treated type 1 and db/db type 2 diabetes model were established, AKI model was induced in mice by ischemia-reperfusion injury(IRI). Mouse proximal tubular cell cells were subjected to high glucose and hypoxia-reoxygenation in vitro. Transcriptional RNA Sequencing was performed for clustering analysis and target gene screening. Renal structural damage was determined by histological staining, whereas creatinine and urea nitrogen levels were used to measure renal function.

Results: Deteriorated renal function and renal tissue damage were observed in AKI mice with diabetic background. RNA Sequencing showed a decrease in fatty acid oxidation (FAO) pathway and an increase in abnormal glycolysis. Treatment with Dapa, Sitagliptin(a DPP-4 Inhibitor)and Insulin reduced blood glucose levels in mice, and improved renal function. However, Dapa had a superior therapeutic effect and alleviated aberrant FAO and glycosis. Dapa reduced cellular death in cultured cells under high glucose hypoxia-reoxygenation conditions, alleviated FAO dysfunction, and reduced abnormal glycolysis. RNA Sequencing showed that SIRT3 expression was reduced in diabetic IRI, which was largely restored by Dapa intervention. 3-TYP, a SIRT3 Inhibitor, reversed the renal protective effects of Dapa and mediated abnormal FAO and glycolysis in mice and tubular cells.

Conclusion: Our study provides experimental evidence for the use of Dapa as a means to reduce diabetic AKI by ameliorating metabolic reprogramming in renal tubular cells.

Keywords

Acute kidney injury; Dapagliflozin; Diabetes; Metabolic reprogramming; SIRT3.

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