Date: Sunday, June 2, 2019
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall C & D
*Purpose: IRI is a major source of morbidity after renal transplantation, contributing to poor transplant outcomes and decreased graft survival. Histone deacetylases (HDACs) are enzymes responsible for the epigenetic modification of histones and other nuclear proteins, thereby altering gene expression and regulating diverse cellular processes. We have previously shown by individual targeting of 3 class I HDACs (HDAC1, HDAC2 HDAC3) that HDAC2 deletion has a protective effect during renal IRI. However, there are no HDAC2-specific inhibitors (HDACi). We now report data concerning the role of HDAC8, the last remaining Class I HDAC, in renal IRI.
*Methods: We used whole-body tamoxifen-inducible HDAC-8 deficient (HDAC8 KO) and control tamoxifen-treated WT female mice, as well as B6 female mice treated with HDAC8i or DMSO control. Mice were subjected to 28 minutes of warm renal IRI through unilateral clamping of the renal pedicle and contralateral nephrectomy under strict temperature control. Creatinine and BUN were examined at 24-, 48-, 72-, and 96-hours post-IRI.
*Results: After renal IRI, HDAC8 KO (1A & 1B) and HDAC8i-treated (1C & 1D) mice developed significantly less renal injury than controls.
*Conclusions: Both HDAC8 deletion and pharmacologic inhibition are protective in a standardized model of renal IRI. The benefit of HDAC8 pharmacologic inhibition is especially robust, as this is the first HDAC target with this degree of observed benefit. While further clinical correlation and mechanistic understanding are needed, these data highlight the translational potential for selective HDAC8 targeting in prevention of renal injury.
To cite this abstract in AMA style:Hernandez PT, Concors SJ, Aufhauser DD, Krumeich L, Wang Z, Ge G, Beeler A, Levine M, Hancock W. Histone Deacetylase-8 (HDAC8) Inhibition is Protective in a Murine Model of Renal Ischemia Reperfusion Injury (IRI) [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/histone-deacetylase-8-hdac8-inhibition-is-protective-in-a-murine-model-of-renal-ischemia-reperfusion-injury-iri/. Accessed May 8, 2021.
« Back to 2019 American Transplant Congress