2. Academic Validation
  3. Regulation of pericyte metabolic reprogramming restricts the AKI to CKD transition

Regulation of pericyte metabolic reprogramming restricts the AKI to CKD transition

  • Metabolism. 2023 May 23;155592. doi: 10.1016/j.metabol.2023.155592.
Cheng Xu 1,  Quan Hong 2,  Kaiting Zhuang 2,  Xuejing Ren 2,  Shaoyuan Cui 2,  Zheyi Dong 2,  Qian Wang 2,  Xueyuan Bai 3,  Xiangmei Chen 4
Affiliations

Affiliations

  • 1 Department of Nephrology, The Second Hospital of Jilin University, Nanguan District, Changchun 130041, Jilin, China; Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Beijing Key Laboratory of Kidney Disease, Haidian District, Beijing 100853, China.
  • 2 Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Beijing Key Laboratory of Kidney Disease, Haidian District, Beijing 100853, China.
  • 3 Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Beijing Key Laboratory of Kidney Disease, Haidian District, Beijing 100853, China. Electronic address: xueyuan_bai@163.com.
  • 4 Department of Nephrology, The Second Hospital of Jilin University, Nanguan District, Changchun 130041, Jilin, China; Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Beijing Key Laboratory of Kidney Disease, Haidian District, Beijing 100853, China. Electronic address: xmchen301@126.com.
PMID: 37230215 DOI: 10.1016/j.metabol.2023.155592
Abstract

Background and aims: Acute kidney injury (AKI) is associated with high morbidity and mortality and is recognized as a long-term risk factor for progression to chronic kidney disease (CKD). The AKI to CKD transition is characterized by interstitial fibrosis and the proliferation of collagen-secreting myofibroblasts. Pericytes are the major source of myofibroblasts in kidney fibrosis. However, the underlying mechanism of pericyte-myofibroblast transition (PMT) is still unclear. Here we investigated the role of metabolic reprogramming in PMT.

Methods: Unilateral ischemia/reperfusion-induced AKI to CKD mouse model and TGF-β-treated pericyte-like cells were used to detect the levels of fatty acid oxidation (FAO) and glycolysis, and the critical signaling pathways during PMT under the treatment of drugs regulating metabolic reprogramming.

Results: PMT is characterized by a decrease in FAO and an increase in glycolysis. Enhancement of FAO by the Peroxisome Proliferator-activated Receptor gamma coactivator-1α (PGC1α) activator ZLN-005 or suppression of glycolysis by the Hexokinase 2 (HK2) inhibitor 2-DG can inhibit PMT, preventing the transition of AKI to CKD. Mechanistically, AMPK modulates various pathways involved in the metabolic switch from glycolysis to FAO. Specifically, the PGC1α-CPT1A pathway activates FAO, while inhibition of the HIF1α-HK2 pathway drives glycolysis inhibition. The modulations of these pathways by AMPK contribute to inhibiting PMT.

Conclusions: Metabolic reprogramming controls the fate of pericyte transdifferentiation and targets the abnormal metabolism of pericytes can effectively prevent AKI to CKD transition.

Keywords

Acute kidney injury; Chronic kidney disease; Fatty acid oxidation; Fibrosis; Glycolysis; Pericyte-myofibroblast transition.

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