# HDAC2 Inhibition Mitigates Renal Ischemia Reperfusion Injury

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $362,934

## Abstract

Project Summary
Renal ischemia reperfusion injury (IRI) is a major source of medical morbidity and mortality, affecting diverse
medical scenarios including transplantation, cardiac arrest, cardiopulmonary bypass, trauma, and vascular
surgery. Despite the use of preservation solution and minimization of organ ischemia time, early allograft
dysfunction occurs in at least 30% of deceased donor transplant recipients and this number is rising with the
enhanced use of marginal organ donors. Impaired early graft function impacts long term graft performance
and graft loss is a predictor of death. Despite significant efforts, no specific therapies to mitigate ischemic
injury have reached clinical use. We have identified that inhibition of histone/protein deacetylases (HDACs), a
family of proteins that remove acetyl groups from DNA-associated histone proteins as well as other groups of
proteins, is effective in mitigating early renal functional impairment and the development of fibrosis after renal
IRI. We have narrowed the specificity of this beneficial effect to the nuclear class I HDACs which tightly
regulate broad patterns of gene expression. We have subsequently identified that HDAC2 deletion, even when
confined to the kidney itself, conveys major protection from ischemia reperfusion injury. Conversely, deletion
of closely homologous HDAC1 leads to impaired renal IRI tolerance. We thus propose to identify the
mechanism behind the HDAC2 deletion effect with the intent of translating this benefit to clinically relevant
scenarios of renal ischemia such as transplantation and cardiopulmonary bypass. Our proposal uses whole
animal, cellular, and molecular approaches to define the role that class I HDACs play in renal ischemia
tolerance. We will define remaining unanswered questions such as tissue specificity of effects in cold ischemia
transplant models, understand tissue specificity by confining HDAC deletion to renal tubular epithelium, and
use innovative hyperpolarized 13C MRI to identify if HDACs are altering in vivo metabolism. We will then use
cellular approaches to assess whether inhibiting the deacetylase function of HDAC2 can reproduce the
deletion effects, with the possibility of focusing translational targets on deacetylase inhibitors. Lastly, we will
utilize molecular approaches to identify the impact that HDAC2 deletion has on nuclear corepressor complex
formation, localization, and DNA binding, further highlighting possible mechanisms for future translation. Our
studies intend to translate a highly novel finding of a single HDAC knockout drastically improving in vivo renal
ischemia tolerance to a clinically approachable process by better understanding how the in vivo effects are
achieved. This may have major impact on the development of strategies to minimize renal ischemic damage,
which is a major source of cost and comorbidity in our health system.

## Key facts

- **NIH application ID:** 9975142
- **Project number:** 5R01DK106243-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Matthew Howard Levine
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $362,934
- **Award type:** 5
- **Project period:** 2016-08-20 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975142

## Citation

> US National Institutes of Health, RePORTER application 9975142, HDAC2 Inhibition Mitigates Renal Ischemia Reperfusion Injury (5R01DK106243-05). Retrieved via AI Analytics 2026-05-31 from https://api.ai-analytics.org/grant/nih/9975142. Licensed CC0.

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