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.

Histone deacetylase-2 controls IL-1β production through the regulation of NLRP3 expression and activation in tuberculosis infection

“…The similar results were also obtained with the cells stimulated with LPS/CD40LT for IL-1β production although with visible effects of DHOB ( Figure 7 C). Because HDAC2 exhibits 85% of total sequence identity with HDAC1 ( Grozinger and Schreiber, 2002 ) as also shown in Figure 6 A and DHOB reduced HDAC activities of both HDAC1 and HDAC2, to further confirm this effect of HDAC2, we used BRD6688, a chemical inhibitor of HDAC2 with longer effects in both in vitro and in vivo models ( Aufhauser et al., 2021 ; Wagner et al., 2015 ), to test the effect of blocking HDAC2 on IL-1β production by Mtb -infected human MDM. Our results demonstrated that blocking HDAC2 with BRD6688 significantly increased the production of IL-1β by MDM compared with the cells treated with DMSO control in a concentration-dependent manner, with 0.25–1.0 μM already showing significantly increased IL-1β production and gradual reduced effects with 2.5–5.0 μM concentration ( Figure 7 D).…”

Identification of hub genes associated with acute kidney injury induced by renal ischemia–reperfusion injury in mice

“…Data GSE39548 ( Correa-Costa et al, 2012 ) used the GPL7202 platform (Agilent-014868 Whole Mouse Genome Microarray) which included four IRI-AKI and four control samples. Data GSE131288 ( Aufhauser et al, 2021 ) used the GPL16570 platform (Affymetrix Mouse Gene 2.0 ST Array) which included three IRI-AKI and three control samples. GEO databases were provided as the raw data.…”

“…The present study aimed to gain an in-depth understanding of its mechanism and identify potential molecular markers for prognosis and early detection, as well as drug targets for the treatment of AKI. Two datasets [GSE39548 ( Correa-Costa et al, 2012 ) and GSE131288 ( Aufhauser et al, 2021 )] were downloaded and analyzed from the Gene Expression Omnibus (GEO) database to identify genes that are differentially expressed (DEGs) in AKI caused by IRI. Functional enrichment analysis and protein-protein interaction (PPI) network construction were performed for the targeted genes.…”

Identification of hub genes and transcription factor-miRNA-mRNA pathways in mice and human renal ischemia-reperfusion injury

“…The mRNA expression profiles ( ( Correa-Costa et al, 2012 ), ( Liu et al, 2014 ), ( Nezu, Suzuki & Yamamoto, 2017 ), ( Markó et al., 2016 ) and ( Aufhauser et al, 2021 )) and the miRNA expression profile ( ( Shapiro et al, 2011 )) datasets were downloaded from the GEO database ( ) ( Barrett et al, 2013 ). All of the datasets included renal IRI groups and control groups.…”