2. Academic Validation
  3. The PI3K-Akt-mTOR pathway mediates renal pericyte-myofibroblast transition by enhancing glycolysis through HKII

The PI3K-Akt-mTOR pathway mediates renal pericyte-myofibroblast transition by enhancing glycolysis through HKII

  • J Transl Med. 2023 May 13;21(1):323. doi: 10.1186/s12967-023-04167-7.
Liangmei Chen # 1 2,  Xiaofan Li # 1,  Yiyao Deng 3,  Jianwen Chen 1,  Mengjie Huang 1,  Fengge Zhu 1,  Zhumei Gao 1,  Lingling Wu 1,  Quan Hong 1,  Zhe Feng 1,  Guangyan Cai 1,  Xuefeng Sun 1,  Xueyuan Bai 4,  Xiangmei Chen 5
Affiliations

Affiliations

  • 1 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, The First Affiliated Hospital of Jinan University, Jinan University, Tianhe District, Guangzhou, 510632, Guangdong, China.
  • 3 Department of Nephrology, Guizhou Provincial People's Hospital, Guiyang, 550002, Guizhou, China.
  • 4 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. xueyuan_bai@163.com.
  • 5 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. xmchen301@126.com.
  • # Contributed equally.
PMID: 37179292 DOI: 10.1186/s12967-023-04167-7
Abstract

Background: Pericyte-myofibroblast transition (PMT) has been confirmed to contribute to renal fibrosis in several kidney diseases, and transforming growth factor-β1 (TGF-β1) is a well-known cytokine that drives PMT. However, the underlying mechanism has not been fully established, and little is known about the associated metabolic changes.

Methods: Bioinformatics analysis was used to identify transcriptomic changes during PMT. PDGFRβ + pericytes were isolated using MACS, and an in vitro model of PMT was induced by 5 ng/ml TGF-β1. Metabolites were analyzed by ultraperformance liquid chromatography (UPLC) and tandem mass spectrometry (MS). 2-Deoxyglucose (2-DG) was used to inhibit glycolysis via its actions on Hexokinase (HK). The Hexokinase II (HKII) plasmid was transfected into pericytes for HKII overexpression. LY294002 or rapamycin was used to inhibit the PI3K-Akt-mTOR pathway for mechanistic exploration.

Results: An increase in carbon metabolism during PMT was detected through bioinformatics and metabolomics analysis. We first detected increased levels of glycolysis and HKII expression in pericytes after stimulation with TGF-β1 for 48 h, accompanied by increased expression of α-SMA, vimentin and desmin. Transdifferentiation was blunted when pericytes were pretreated with 2-DG, an inhibitor of glycolysis. The phosphorylation levels of PI3K, Akt and mTOR were elevated during PMT, and after inhibition of the PI3K-Akt-mTOR pathway with LY294002 or rapamycin, glycolysis in the TGF-β1-treated pericytes was decreased. Moreover, PMT and HKII transcription and activity were blunted, but the plasmid-mediated overexpression of HKII rescued PMT inhibition.

Conclusions: The expression and activity of HKII as well as the level of glycolysis were increased during PMT. Moreover, the PI3K-Akt-mTOR pathway regulates PMT by increasing glycolysis through HKII regulation.

Keywords

Glycolysis; HKII; PI3K-Akt-mTOR pathway; Pericyte-myofibroblast transition; TGF-β1.

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