Histone deacetylase modulates the proinflammatory and -fibrotic changes in tubulointerstitial injury

Takeshi Marumo, Keiichi Hishikawa, Masahiro Yoshikawa, Junichi Hirahashi, Shoji Kawachi, Toshiro Fujita

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

Histone deacetylase (HDAC) regulates gene expression by modifying chromatin structure. Although changes in the expression and activities of HDAC may affect the course of kidney disease, the role of HDAC in tubulointerstitial injury has not been explored. We therefore investigated the alterations in HDAC expression and determined the effects of HDAC inhibition on the tubulointerstitial injury induced by unilateral ureteral obstruction. The induction of HDAC1 and HDAC2, accompanied by a decrease in histone acetylation was observed in kidneys injured by ureteral obstruction. Immunohistochemical analysis revealed that HDAC1 and HDAC2 were induced in renal tubular cells. Treatment with an HDAC inhibitor, trichostatin A (TSA), attenuated macrophage infiltration and fibrotic changes in tubulointerstitial injury induced by ureteral obstruction. The induction of colony-stimulating factor-1 (CSF-1), a chemokine known to be involved in macrophage infiltration in tubulointerstitial injury, was reduced in injured kidneys from mice treated with TSA. TSA, valproate, and the knockdown of HDAC1 or HDAC2 significantly reduced CSF-1 induced by TNF-α in renal tubular cells. These results suggest that tubular HDAC1 and HDAC2, induced in response to injury, may contribute to the induction of CSF-1 and the initiation of macrophage infiltration and profibrotic responses. These findings suggest a potential of HDAC inhibition therapy aimed at reducing inflammation and fibrosis in tubulointerstitial injury.

Original languageEnglish
Pages (from-to)F133-F141
JournalAmerican Journal of Physiology - Renal Physiology
Volume298
Issue number1
DOIs
Publication statusPublished - 2010 Jan 1
Externally publishedYes

Keywords

  • Chemokine
  • Epigenetic
  • Ureteral obstruction

ASJC Scopus subject areas

  • Physiology
  • Urology

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