Glycolysis inhibitors suppress renal interstitial fibrosis via divergent effects on fibroblasts and tubular cells
Open accessAbstract
Renal interstitial fibrosis is a common pathological feature of chronic kidney disease that may involve changes of metabolism in kidney cells. In the present study, we first showed that blockade of glycolysis with either dichloroacetate (DCA) or shikonin to target different glycolytic enzymes reduced renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO). Both inhibitors evidently suppressed the induction of fibronectin and collagen type I in obstructed kidneys, with DCA also showing inhibitory effects on collagen type IV and α-smooth muscle actin (α-SMA). Histological examination also confirmed less collagen deposition in DCA-treated kidneys. Both DCA and shikonin significantly inhibited renal tubular apoptosis but not interstitial apoptosis in UUO. Macrophage infiltration after UUO injury was also suppressed. Shikonin, but not DCA, caused obvious animal weight loss during UUO. To determine whether shikonin and DCA worked on tubular cells and/or fibroblasts, we tested their effects on cultured renal proximal tubular BUMPT cells and renal NRK-49F fibroblasts during hypoxia or transforming growth factor-β 1 treatment. Although both inhibitors reduced fibronectin and α-SMA production in NRK-49F cells during hypoxia or transforming growth factor-β 1 treatment, they did not suppress fibronectin and α-SMA expression in BUMPT cells. Altogether, these results demonstrate the inhibitory effect of glycolysis inhibitors on renal interstitial fibrosis. In this regard, DCA is more potent for fibrosis inhibition and less toxic to animals than shikonin.
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A disease-associated subpopulation with a transitional gene expression profile intermediate between monocyte-derived and alveolar macrophages was uncovered.
“uncovered a disease-associated subpopulation with a transitional gene expression profile intermediate between monocyte-derived and alveolar macrophages.”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [70]
A pathological subgroup of transitional macrophages is required for the fibrotic response to injury in murine bleomycin-induced lung fibrosis.
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From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [70]
Human orthologs of genes expressed by these transitional macrophages are upregulated in samples from patients with idiopathic pulmonary fibrosis.
“human orthologs of genes expressed by these transitional macrophages were upregulated in samples from patients with idiopathic pulmonary fibrosis70.”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [70]
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 [70]
CX3CR1+SiglecF+ transitional macrophages localize to the fibrotic niche and are profibrotic in vivo.
“These CX3CR1+SiglecF+ transitional macrophages localized to the fibrotic niche and were profibrotic in vivo.”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [70]
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Fibrosis: from mechanisms to medicines
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- Authors
- Wei, Q., Su, J., Dong, G., Zhang, M., Huo, Y., & Dong, Z.
- Affiliations
- Augusta University (US)
- Corresponding author
- Dong, Guie
- Dong, Zheng
- Venue
- American Journal of Physiology-Renal Physiology
- Publisher
- American Physiological Society
- Published
- 2019-06-01
- Volume
- 316
- Issue
- 6
- Pages
- F1162-F1172
- ISSN
- 1522-1466 (ISSN-L)
- 1931-857X
- PMC
- PMC6620587
- OpenAlex
- W2940438627
- Cited by
- 122
- References
- 39
- Citations by year
- 2026: 10 · 2025: 16 · 2024: 24 · 2023: 22 · 2022: 16 · 2021: 20 · 2020: 12 · 2019: 2
- FWCI
- 9.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Renal Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (058831, 087843)
- U.S. Department of Veterans Affairs (VA) (000319)
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- tubulointerstitial fibrosis, glycolysis inhibitors, dichloroacetate, shikonin, chronic kidney disease, unilateral ureteral obstruction, renal fibroblasts, proximal tubular epithelial cells, tubular apoptosis, macrophage infiltration, fibronectin, type I collagen, type IV collagen, alpha-smooth muscle actin, hypoxia, TGF-β1, drug toxicity
- MeSH terms
- Animals, Cell Line, Dichloroacetic Acid, Disease Models, Animal, Enzyme Inhibitors, Epithelial Cells, Extracellular Matrix, Fibroblasts, Fibrosis, Glycolysis, Kidney Diseases, Kidney Tubules, Macrophages, Male, Mice, Inbred C57BL, Naphthoquinones, Ureteral Obstruction, Signal Transduction, Apoptosis, Mice
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