TY - JOUR
T1 - Glycolysis inhibitors suppress renal interstitial fibrosis via divergent effects on fibroblasts and tubular cells
AU - Wei, Qingqing
AU - Su, Jennifer
AU - Dong, Guie
AU - Zhang, Ming
AU - Huo, Yuqing
AU - Dong, Zheng
N1 - Funding Information:
This work was supported partly by the Augusta University Extramural Success Award, National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-058831 and DK-087843, and Department of Veterans Affairs Grant BX000319. Z. Dong is a recipient of the Senior Research Career Scientist award from the Department of Veterans Affairs.
Publisher Copyright:
© 2019, American Physiological Society. All rights reserved.
PY - 2019
Y1 - 2019
N2 - Wei Q, Su J, Dong G, Zhang M, Huo Y, Dong Z. Glycolysis inhibitors suppress renal interstitial fibrosis via divergent effects on fibroblasts and tubular cells. Am J Physiol Renal Physiol 316: F1162– F1172, 2019. First published April 10, 2019; doi:10.1152/ajpre-nal.00422.2018.—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-β1 treatment. Although both inhibitors reduced fibronectin and α-SMA production in NRK-49F cells during hypoxia or transforming growth factor-β1 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.
AB - Wei Q, Su J, Dong G, Zhang M, Huo Y, Dong Z. Glycolysis inhibitors suppress renal interstitial fibrosis via divergent effects on fibroblasts and tubular cells. Am J Physiol Renal Physiol 316: F1162– F1172, 2019. First published April 10, 2019; doi:10.1152/ajpre-nal.00422.2018.—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-β1 treatment. Although both inhibitors reduced fibronectin and α-SMA production in NRK-49F cells during hypoxia or transforming growth factor-β1 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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U2 - 10.1152/ajprenal.00422.2018
DO - 10.1152/ajprenal.00422.2018
M3 - Article
C2 - 30969803
AN - SCOPUS:85067101835
SN - 0363-6127
VL - 316
SP - F1162-F1172
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 6
ER -