Elucidating the Mechanisms of Kidney Regeneration and Therapeutic Augmentation

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is a serious disorder that involves a rapid decline in renal function over a short period of hours to days. These events are becoming increasingly common in hospitalized patients and are associated with significant morbidity and mortality. Severe cases can result in end-stage renal disease, and evidence suggests that AKI is a precursor to long-term renal impairment. US healthcare costs associated with these events reach several billion dollars annually. Despite these costs, there are no targeted clinical treatments for AKI. Specifically, no therapies exist that accelerate renal recovery or decrease fibrosis when administered after injury. However, the mammalian kidney possesses an inherent capacity to regenerate after AKI. This process involves the dedifferentiation of surviving tubular epithelial cells that proliferate to repopulate injured area. Therefore, a promising approach to ameliorating AKI-mediated damage lies in developing novel therapies that can enhance these regenerative processes post-AKI. The work outlined in this proposal will elucidate the mechanisms involved in kidney regeneration after AKI by evaluating the ability of a novel class of histone deacetylase inhibitors (HDACis), the phenylthiobutanoic acids, to augment renal regeneration. We have previously shown that a specific compound in this class, methyl 4-(phenylthio)butanoate (m4PTB), enhances tubular cell proliferation and renal regeneration when administered post-injury in both zebrafish and mouse AKI models. This work will provide mechanistic insight into the signaling pathways involved in kidney regeneration post-AKI by examining the role of HDACi-stimulated signaling in promoting renal proliferation and survival in zebrafish larvae. Given the significant healthcare burden posed by AKI, these are critical initial steps in order to improve the treatment options available to patients.