Epigenetic regulation of BMP7 in the regenerative response to ischemia.
Kidneys damaged by ischemia have the potential to regenerate through a mechanism involving intrarenal induction of protective factors, including bone morphogenetic protein-7 (BMP7). Epigenetic changes, such as alterations in histone modifications, have also been shown to play a role in various pathologic conditions, but their involvement in ischemic injury and regeneration remains unknown. This study investigated whether changes in histone acetylation, regulated by histone acetyltransferase and histone deacetylase (HDAC), are induced by renal ischemia and involved in the regenerative response. Ischemia/reperfusion of the mouse kidney induced a transient decrease in histone acetylation in proximal tubular cells, likely as a result of a decrease in histone acetyltransferase activity as suggested by experiments with energy-depleted renal epithelial cells in culture. During recovery after transient energy depletion in epithelial cells, the HDAC isozyme HDAC5 was selectively downregulated in parallel with the return of acetylated histone. Knockdown of HDAC5 by RNAi significantly increased histone acetylation and BMP7 expression. BMP7 induction and HDAC5 downregulation in the recovery phase were also observed in proximal tubular cells in vivo after transient ischemia. These data indicate that ischemia induces dynamic epigenetic changes involving HDAC5 downregulation, which contributes to histone re-acetylation and BMP7 induction in the recovery phase. This highlights HDAC5 as a modulator of the regenerative response after ischemia and suggests HDAC5 inhibition may be a therapeutic strategy to enhance BMP7 expression.
Marumo
Takeshi
T
Department of Clinical Renal Regeneration and Division of Nephrology and Endocrinology, Department of Internal Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku 113-8655 Tokyo, Japan. tmarumo-npr@umin.ac.jp
Hishikawa
Keiichi
K
Yoshikawa
Masahiro
M
Fujita
Toshiro
T
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000968:Antimycin A / Q000494:pharmacology; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005260:Female; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply / Q000502:physiology*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D051379:Mice; D010085:Oxidative Phosphorylation / Q000187:drug effects; D051381:Rats; D012038:Regeneration / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D000900:Anti-Bacterial Agents; C525821:Bmp7 protein, rat; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D006657:Histones; D016212:Transforming Growth Factor beta; D000968:Antimycin A; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases