HDAC2 targeting stabilizes the CoREST complex in renal tubular cells and protects against renal ischemia/reperfusion injury.

Abstract

Histone/protein deacetylases (HDAC) 1 and 2 are typically viewed as structurally and functionally similar enzymes present within various co-regulatory complexes. We tested differential effects of these isoforms in renal ischemia reperfusion injury (IRI) using inducible knockout mice and found no significant change in ischemic tolerance with HDAC1 deletion, but mitigation of ischemic injury with HDAC2 deletion. Restriction of HDAC2 deletion to the kidney via transplantation or PAX8-controlled proximal renal tubule-specific Cre resulted in renal IRI protection. Pharmacologic inhibition of HDAC2 increased histone acetylation in the kidney but did not extend renal protection. Protein analysis demonstrated increased HDAC1-associated CoREST protein in HDAC2-/- versus WT cells, suggesting that in the absence of HDAC2, increased CoREST complex occupancy of HDAC1 can stabilize this complex. In vivo administration of a CoREST inhibitor exacerbated renal injury in WT mice and eliminated the benefit of HDAC2 deletion. Gene expression analysis of endothelin showed decreased endothelin levels in HDAC2 deletion. These data demonstrate that contrasting effects of HDAC1 and 2 on CoREST complex stability within renal tubules can affect outcomes of renal IRI and implicate endothelin as a potential downstream mediator.

• Authors: David D Aufhauser Jr, Paul Hernandez, Seth J Concors, Ciaran O'Brien, Zhonglin Wang, Douglas R Murken, Arabinda Samanta, Ulf H Beier, Lauren Krumeich, Tricia R Bhatti, Yanfeng Wang, Guanghui Ge, Liqing Wang, Shayan Cheraghlou, Florence F Wagner, Edward B Holson, Jay H Kalin, Philip A Cole, Wayne W Hancock, Matthew H Levine
• Journal: Scientific reports (Sci Rep) Vol. 11 Issue 1 Pg. 9018 (04 27 2021) ISSN: 2045-2322 [Electronic] England
• PMID: 33907245 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Co-Repressor Proteins
• Endothelins
• Enzyme Inhibitors
• Isoenzymes
• Rcor2 protein, mouse
• Hdac1 protein, mouse
• Hdac2 protein, mouse
• Histone Deacetylase 1
• Histone Deacetylase 2

Topics

• Animals
• Co-Repressor Proteins (antagonists & inhibitors, metabolism)
• Endothelins (metabolism)
• Enzyme Inhibitors (pharmacology)
• Female
• Gene Deletion
• Histone Deacetylase 1 (antagonists & inhibitors, genetics, metabolism)
• Histone Deacetylase 2 (antagonists & inhibitors, genetics, metabolism)
• Isoenzymes (antagonists & inhibitors, metabolism)
• Kidney Tubules, Proximal (drug effects, metabolism)
• Male
• Mice
• Mice, Knockout
• Reperfusion Injury (prevention & control)