BRCA1-mediated DNA repair protects tubular epithelial cells during Acute Kidney Injury

Abstract

Acute kidney injury (AKI) is a common clinical syndrome that is associated with adverse short and long- term sequelae. AKI usually occurs in the setting of other disorders, such as sepsis, rhabdomyolysis, and cardiovascular and oncological diseases, where the underlying disease and or associated therapy cause an abrupt loss of renal function. While the underlying pathophysiological mechanisms are incompletely understood, renal tubular epithelial cell (RTEC) dysfunction and cell-death are the hallmarks and the underlying cause of AKI. Recent studies have shown that DNA damage contributes to RTEC dysfunction during AKI. However, due to the technical challenges in studying DNA repair in vivo, it remains unknown if RTECs can repair their DNA during or after AKI. Here we have used a novel DNA repair reporter mouse to demonstrate that functional homologous recombination (HR) mediated DNA repair occurs in RTECs early during the development of Ischemia-reperfusion associated AKI. Importantly, RTEC-specific deletion of HR-linked DNA repair protein, BRCA1 exacerbates RTEC dysfunction and AKI in both male and female mice. Overall, our studies suggest that DNA repair pathways play a protective role during acute kidney injury and are a promising target for therapeutic interventions. The current study was supported by an American Heart Association Predoctoral Fellowship (AHA-900765) to J.A.S and NIDDK 1R01DK132230 to N.P. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.