# Project 3: Intercepting Renal Damage following Skin Exposure to Arsenicals

> **NIH NIH U54** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $575,273

## Abstract

Arsenicals are an important category of chemical weapons due to their devastating effects on the skin as well
as systemic effects damaging multiple organs including the kidney and lung. This project is based on our
findings that cutaneous exposure to lewisite, an arsenical first synthesized during world war I, not only
damages skin but is also rapidly absorbed and exerts toxic effects in the kidney leading to both acute and
delayed kidney damage. Preliminary studies demonstrate that arsenicals cause epigenetic histone remodeling
by hyperacetylation and recruitment of BRD4 to promoter regions of inducible genes associated with
inflammation and tissue damage. BRD4 is a member of the bromo- and extra-terminal domain family of
proteins. In addition, we observed marked upregulation of the cytoprotective protein, heme oxygenase-1 (HO-
1) in the kidney following topical exposure to lewisite. Arsenicals induce higher expression of BRD4 and
inflammatory signaling genes in HO-1 knockout mice as compared to wild-type littermates, suggesting the
importance of HO-1 in epigenetic regulation of inflammatory responses. Taken together, these studies
underscore the significance of both acute and delayed kidney damage following a single cutaneous arsenical
exposure and identify two potential inter-related molecular targets, BRD4 and HO-1 in renal injury.
 The overall goal of this project is to develop mechanism-based post-exposure countermeasures that
can mitigate arsenical-induced kidney damage. Our hypothesis is that toxic doses of arsenicals cause
acetylation of proteins (histones) and subsequent recruitment of bromodomain proteins resulting in activation
of injury pathways and that blocking bromodomain signaling or its downstream effectors can mitigate kidney
injury. In Aim 1, an arsenical mediated murine model of AKI will be characterized to determine the dose- and
time-dependence of kidney damage. In Aim 2, we determine the mechanisms by which arsenicals cause AKI
focusing on BRD4 and HO-1 for intervention in arsenicals-induced AKI. In Aim 3, we will develop targeted
therapeutic intervention in arsenical-induced AKI to determine the optimal window for the beneficial effects by
post-exposure treatment in animals exposed to arsenicals. Both FDA approved and novel small molecules will
be assessed in this aim. Successful completion of our research as proposed here will not only provide an
effective antidote for chemical injury but will also contribute to a broader understanding of how endogenous
epigenetic responses can be exploited towards developing new therapeutic strategies for AKI.

## Key facts

- **NIH application ID:** 10249115
- **Project number:** 5U54ES030246-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** ANUPAM AGARWAL
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $575,273
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249115

## Citation

> US National Institutes of Health, RePORTER application 10249115, Project 3: Intercepting Renal Damage following Skin Exposure to Arsenicals (5U54ES030246-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10249115. Licensed CC0.

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