Class I HDAC activity is required for renal protection and regeneration after acute kidney injury.

Activation of histone deacetylases (HDACs) is required for renal epithelial cell proliferation and kidney development. However, their role in renal tubular cell survival and regeneration after acute kidney injury (AKI) remains unclear. In this study, we demonstrated that all class I HDAC isoforms (1, 2, 3, and 8) were expressed in the renal epithelial cells of the mouse kidney. Inhibition of class I HDACs with MS-275, a highly selective inhibitor, resulted in more severe tubular injury in the mouse model of AKI induced by folic acid or rhabdomyolysis, as indicated by worsening renal dysfunction, increased neutrophil gelatinase-associated lipocalin expression, and enhanced apoptosis and caspase-3 activation. Blocking class I HDAC activity also impaired renal regeneration as evidenced by decreased expression of renal Pax-2, vimentin, and proliferating cell nuclear antigen. Injury to the kidney is accompanied by increased phosphorylation of epidermal growth factor receptor (EGFR), signal transducers and activators of transcription 3 (STAT3), and Akt. Inhibition of class I HDACs suppressed EGFR phosphorylation as well as reduced its expression. MS-275 was also effective in inhibiting STAT3 and Akt phosphorylation, but this treatment did not affect their expression levels. Taken together, these data suggest that the class I HDAC activity contributes to renal protection and functional recovery and is required for renal regeneration after AKI. Furthermore, renal EGFR signaling is subject to regulation by this class of HDACs.

Tang J ，Yan Y ，Zhao TC ，Gong R ，Bayliss G ，Yan H ，Zhuang S ... -  《-》

Class I histone deacetylase activity is required for proliferation of renal epithelial cells.

Tang J ，Yan Y ，Zhao TC ，Bayliss G ，Yan H ，Zhuang S ... -  《-》

EGFR activity is required for renal tubular cell dedifferentiation and proliferation in a murine model of folic acid-induced acute kidney injury.

He S ，Liu N ，Bayliss G ，Zhuang S ... -  《-》

Blocking the class I histone deacetylase ameliorates renal fibrosis and inhibits renal fibroblast activation via modulating TGF-beta and EGFR signaling.

Liu N ，He S ，Ma L ，Ponnusamy M ，Tang J ，Tolbert E ，Bayliss G ，Zhao TC ，Yan H ，Zhuang S ... -  《PLoS One》

Pharmacological inhibition of the mixed lineage leukemia 1-menin interaction aggravates acute kidney injury induced by folic acid and ischemia-reperfusion in mice.

Hou X ，Cui B ，Qiu A ，Liu N ，Zhuang S ... -  《-》