PMID- 37179292 OWN - NLM STAT- MEDLINE DCOM- 20230515 LR - 20230522 IS - 1479-5876 (Electronic) IS - 1479-5876 (Linking) VI - 21 IP - 1 DP - 2023 May 13 TI - The PI3K-Akt-mTOR pathway mediates renal pericyte-myofibroblast transition by enhancing glycolysis through HKII. PG - 323 LID - 10.1186/s12967-023-04167-7 [doi] LID - 323 AB - BACKGROUND: Pericyte-myofibroblast transition (PMT) has been confirmed to contribute to renal fibrosis in several kidney diseases, and transforming growth factor-beta1 (TGF-beta1) 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. PDGFRbeta + pericytes were isolated using MACS, and an in vitro model of PMT was induced by 5 ng/ml TGF-beta1. 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-beta1 for 48 h, accompanied by increased expression of alpha-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-beta1-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. CI - (c) 2023. The Author(s). FAU - Chen, Liangmei AU - Chen L AD - 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. AD - Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Tianhe District, Guangzhou, 510632, Guangdong, China. FAU - Li, Xiaofan AU - Li X AD - 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. FAU - Deng, Yiyao AU - Deng Y AD - Department of Nephrology, Guizhou Provincial People's Hospital, Guiyang, 550002, Guizhou, China. FAU - Chen, Jianwen AU - Chen J AD - 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. FAU - Huang, Mengjie AU - Huang M AD - 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. FAU - Zhu, Fengge AU - Zhu F AD - 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. FAU - Gao, Zhumei AU - Gao Z AD - 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. FAU - Wu, Lingling AU - Wu L AD - 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. FAU - Hong, Quan AU - Hong Q AD - 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. FAU - Feng, Zhe AU - Feng Z AD - 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. FAU - Cai, Guangyan AU - Cai G AD - 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. FAU - Sun, Xuefeng AU - Sun X AD - 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. FAU - Bai, Xueyuan AU - Bai X AD - 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. FAU - Chen, Xiangmei AU - Chen X AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230513 PL - England TA - J Transl Med JT - Journal of translational medicine JID - 101190741 RN - 0 (Transforming Growth Factor beta1) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.1.1 (Hexokinase) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - *Transforming Growth Factor beta1/pharmacology/metabolism MH - *Signal Transduction MH - Proto-Oncogene Proteins c-akt/metabolism MH - Hexokinase/metabolism MH - Phosphatidylinositol 3-Kinases/metabolism MH - Pericytes/metabolism MH - Myofibroblasts/metabolism MH - TOR Serine-Threonine Kinases/metabolism MH - Sirolimus MH - Glycolysis PMC - PMC10182641 OTO - NOTNLM OT - Glycolysis OT - HKII OT - PI3K-Akt-mTOR pathway OT - Pericyte-myofibroblast transition OT - TGF-beta1 COIS- The authors declare no competing interests. EDAT- 2023/05/14 01:07 MHDA- 2023/05/15 06:42 PMCR- 2023/05/13 CRDT- 2023/05/13 23:13 PHST- 2022/11/29 00:00 [received] PHST- 2023/04/28 00:00 [accepted] PHST- 2023/05/15 06:42 [medline] PHST- 2023/05/14 01:07 [pubmed] PHST- 2023/05/13 23:13 [entrez] PHST- 2023/05/13 00:00 [pmc-release] AID - 10.1186/s12967-023-04167-7 [pii] AID - 4167 [pii] AID - 10.1186/s12967-023-04167-7 [doi] PST - epublish SO - J Transl Med. 2023 May 13;21(1):323. doi: 10.1186/s12967-023-04167-7.