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Am J Physiol Renal Physiol. 2019 Jan 9. doi: 10.1152/ajprenal.00513.2018. [Epub ahead of print]

TGF-β1 modifies histone acetylation and acetyl-coenzyme A metabolism in renal myofibroblasts.

Author information

1
Department of Nephrology, Royal Melbourne Hospital, Australia.
2
Nephrology, Royal Melbourne Hospital, Australia.

Abstract

Histone acetylation is an important modulator of gene expression in fibrosis. This study examined the effect of the pre-eminent fibrogenic cytokine TGF-b1 on histone 3 (H3) acetylation and its regulatory kinetics in renal myofibroblasts. Fibroblasts propagated from rat kidneys after ureteric obstruction were treated with recombinant TGF-b1 or vehicle for 48 hours. TGF-b1 -induced myofibroblast activation was accompanied by a net decrease in total H3 acetylation, although changes in individual marks were variable. This was paralleled by a generalised reduction in histone acetyltransferases (HAT), and divergent changes in histone deacetylase (HDAC) enzymes at both transcript and protein levels. Globally this was manifest in a reduction in total HAT activity and increase in HDAC activity. TGF-b1 induced a shift in cellular metabolism from oxidative respiration to aerobic glycolysis resulting in reduced acetyl-CoA. The reduction in total H3 acetylation could be rescued by providing exogenous citrate or alternative sources of acetyl-CoA, without ameliorating changes in HAT/HDAC activity. In conclusion, TGF-b1 produces a metabolic reprogramming in renal fibroblasts, with less H3 acetylation through reduced acetylation, increased deacetylation and changes in carbon availability. Our results suggest that acetyl-CoA availability predominates over HAT and HDAC activity as a key determinant of H3 acetylation in response to TGF-b1.

KEYWORDS:

Acetylation; Histone; Kidney; TGF-b1; fibroblast

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