title: Inhibiting aerobic glycolysis suppresses renal interstitial fibroblast activation and renal fibrosis.
abstract: Chronic kidney diseases generally lead to renal fibrosis. Despite great progress having been made in identifying molecular mediators of fibrosis, the mechanism that governs renal fibrosis remains unclear, and so far no effective therapeutic antifibrosis strategy is available. Here we demonstrated that a switch of metabolism from oxidative phosphorylation to aerobic glycolysis (Warburg effect) in renal fibroblasts was the primary feature of fibroblast activation during renal fibrosis and that suppressing renal fibroblast aerobic glycolysis could significantly reduce renal fibrosis. Both gene and protein assay showed that the expression of glycolysis enzymes was upregulated in mouse kidneys with unilateral ureter obstruction (UUO) surgery or in transforming growth factor-β1 (TGF-β1)-treated renal interstitial fibroblasts. Aerobic glycolysis flux, indicated by glucose uptake and lactate production, was increased in mouse kidney with UUO nephropathy or TGF-β1-treated renal interstitial fibroblasts and positively correlated with fibrosis process. In line with this, we found that increasing aerobic glycolysis can remarkably induce myofibroblast activation while aerobic glycolysis inhibitors shikonin and 2-deoxyglucose attenuate UUO-induced mouse renal fibrosis and TGF-β1-stimulated myofibroblast activation. Furthermore, mechanistic study indicated that shikonin inhibits renal aerobic glycolysis via reducing phosphorylation of pyruvate kinase type M2, a rate-limiting glycolytic enzyme associated with cell reliance on aerobic glycolysis. In conclusion, our findings demonstrate the critical role of aerobic glycolysis in renal fibrosis and support treatment with aerobic glycolysis inhibitors as a potential antifibrotic strategy.
authors.affiliation: Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China; and.
authors.forename: Hao
authors.initials: H
authors.lastname: Ding
authors.affiliation: Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China; and.
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China; and.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China; and.
authors.forename: Feng
authors.initials: F
authors.lastname: Bai
authors.affiliation: Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China; and.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China; and.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China; and.
authors.forename: Jing
authors.initials: J
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University Advanced Institute of Life Sciences, Nanjing, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Zen
authors.affiliation: Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China; and jwyang@njmu.edu.cn.
authors.forename: Junwei
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D003847:Deoxyglucose / Q000494:pharmacology*; D004195:Disease Models, Animal; D005355:Fibrosis; D006019:Glycolysis / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D058628:Myofibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009285:Naphthoquinones / Q000494:pharmacology*; D010766:Phosphorylation; D011770:Pyruvate Kinase / Q000378:metabolism; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D013963:Thyroid Hormones / Q000378:metabolism; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014517:Ureteral Obstruction / Q000150:complications; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D003847:Deoxyglucose; D008565:Membrane Proteins; D009285:Naphthoquinones; D011770:Pyruvate Kinase; D013963:Thyroid Hormones; D053773:Transforming Growth Factor beta1; D000097810:Thyroid Hormone-Binding Proteins; C508960:TGFB1 protein, human; C016101:shikonin
keywords: aerobic glycolysis; chronic kidney disease; fibroblast; fibrosis