Inhibiting aerobic glycolysis suppresses renal interstitial fibroblast activation and renal fibrosis
Open accessAbstract
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.
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Several recent studies have identified subpopulations of monocytes and macrophages that can regulate fibrosis and tissue remodelling.
“Several recent studies have identified subpopulations of monocytes and macrophages which have the capacity to regulate fibrosis and tissue remodelling18,61,68–71.”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [69]
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- Authors
- Ding, H., Jiang, L., Xu, J., Bai, F., Zhou, Y., Yuan, Q., Luo, J., Zen, K., & Yang, J.
- Affiliations
- Second Affiliated Hospital of Nanjing Medical University (CN)
- State Key Laboratory of Pharmaceutical Biotechnology (CN)
- Corresponding author
- Yang, Junwei
- Venue
- American Journal of Physiology-Renal Physiology
- Publisher
- American Physiological Society
- Published
- 2017-09-01
- Volume
- 313
- Issue
- 3
- Pages
- F561-F575
- ISSN
- 1522-1466 (ISSN-L)
- 1931-857X
- OpenAlex
- W2591251590
- Cited by
- 250
- References
- 56
- Citations by year
- 2026: 25 · 2025: 29 · 2024: 36 · 2023: 41 · 2022: 31 · 2021: 47 · 2020: 20 · 2019: 13 · 2018: 6 · 2017: 2
- FWCI
- 10.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal of Physiology-Renal Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- 973 Science program of the Ministry of Science and Technology of China (2012CB517603)
- National Science Foundation of China Grants (81470971, 31300955/C1102)
- Key project of National Natural Science Foundation of China (81530022)
- Science Foundation of Jiangsu Province Grants (BK-20141489)
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- aerobic glycolysis, renal fibrosis, renal interstitial fibroblasts, fibroblast activation, myofibroblast activation, Warburg effect, PKM2, shikonin, 2-deoxyglucose, TGF-β1, unilateral ureteral obstruction, antifibrotic therapy, chronic kidney disease, glycolysis inhibitors
- MeSH terms
- Thyroid Hormone-Binding Proteins, Animals, Carrier Proteins, Cell Line, Deoxyglucose, Disease Models, Animal, Fibrosis, Glycolysis, Kidney, Male, Membrane Proteins, Naphthoquinones, Phosphorylation, Pyruvate Kinase, Thyroid Hormones, Time Factors, Ureteral Obstruction, Mice, Rats, Renal Insufficiency, Chronic, Transforming Growth Factor beta1, Myofibroblasts
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