Histone deacetylase modulates the proinflammatory and -fibrotic changes in tubulointerstitial injury.
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-alpha 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.
Marumo
Takeshi
T
Dept. of Clinical Renal Regeneration, and Div. of Nephrology and Endocrinology, Dept. of Internal Medicine, Univ. of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-8655 Tokyo, Japan. tmarumo-npr@umin.ac.jp
Hishikawa
Keiichi
K
Yoshikawa
Masahiro
M
Hirahashi
Junichi
J
Kawachi
Shoji
S
Fujita
Toshiro
T
D000107:Acetylation; D000818:Animals; D004195:Disease Models, Animal; D005355:Fibrosis; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D007684:Kidney Tubules / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009395:Nephritis, Interstitial / Q000201:enzymology* / Q000209:etiology / Q000473:pathology*; D014517:Ureteral Obstruction / Q000150:complications
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C012589:trichostatin A; D016173:Macrophage Colony-Stimulating Factor; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2