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.