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.
