Epigenetic Regulation of BMP7 in the Regenerative Response to Ischemia

Abstract

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.

Saha Suppresses Peritoneal Fibrosis in Mice

“…It has been suggested that BMP-7 suppresses fibrosis by inhibiting TGF-β1 synthesis (36) and by controlling TGF-β signaling via blocking the nuclear translocation of phosphorylated Smad2/3 (37). In fact, the association between BMP-7 and histone acetylation has already been shown (22). Marumo, et al reported that marked induction of BMP-7 and the increase of strongly positive cells for acetylated histone were observed simultaneously in the proximal tubular cells during the recovery phase following renal ischemic reperfusion in mice (22).…”

“…Some reports indicate that the expression of fibrosis inhibitory factors can be increased by promoting histone acetylation (21,22). As the effects of inhibitory factors for fibrosis, Yu et al reported that bone morphogenetic protein 7 (BMP-7) and hepatocyte growth factor (HGF) ameliorated high-glucose-induced epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells (23).…”

Basic helix-loop-helix transcriptional factor MyoR regulates BMP-7 in acute kidney injury

“…The cDNA product was diluted to a volume of 200 l, and 5-l aliquots were used as templates for amplification using the SYBR Green PCR amplification reagent (Applied Biosystems) and gene-specific primers for BMP-7 (forward 5=-CGCTC-CAAGACGCCAAA-3= and reverse 5=-CCTCTGGTCACTGCT-GCTGTT-3=). Specific primers for BMP-7 were designed according to a previous report (13) and were checked to determine whether they showed a single peak in the dissociation curve. Kidney SP cells obtained just after FACS sorting were resuspended in RNAprotect Cell Reagent (Qiagen).…”

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

“…Despite the potential role of HDAC in molecular responses to kidney injury, changes in the expression of HDAC and histone acetylation in the kidney have not been characterized. In this regard, we recently reported that HDAC5 downregulation, which leads to histone acetylation in renal tubular cells, contributes to the regenerative response to ischemia (21).…”