Renal Cell Injury by Ischemia: a role for Bid

Project: Research project

Project Details

Description

Ischemic injury of the kidneys leads to acute renal failure, which, despite intensive research, continues to be
associated with high mortality. While the development of ischemic renal failure involves multiple factors and
may proceed in several phases, it is ultimately precipitated by sublethal and lethal damage to the tubular cells.
However, the molecular basis of tubular cell injury by ischemia remains unclear. The long-term goal of our
research is to identify the key factors that are responsible for tubular cell injury and design effective strategies
to diminish ischemic renal pathology. We showed that ischemic injury of cultured tubular cells involved the
activation of Bax, a death-promoting Bcl-2 family protein. We found recently that Bid, another pro-death
molecule, was activated during renal ischemia. Of interest, Bid could act upstream of Bax, leading to
mitochondrial damage and cell death. Importantly, our preliminary studies demonstrated that ischemictubular
cell injury and renal failure were diminished in Bid knockout mice. Based on these observations, we
hypothesize that Bid, upon activation during renal ischemia, interacts and collaborates with Bax to disrupt
mitochondria, contributing to the development of cell injury, tissue damage and renal failure. We will test this
hypothesis by pursuing three specific aims: (1) to demonstrate conclusive evidence for the involvementof Bid
in ischemic renal injury using Bid knockout models;(2) to determine the role of Bax in ischemic renal injury
and renal failure using Bax knockout models;(3) to determine the physical and functional interactions
between Bid and Bax in renal tubular cells. These studies are expected to demonstrate the regulation of
ischemic renal cell injury by Bid and Bax. They will also provide new insights into cell injury mechanisms
mediated by Bcl-2 family proteins, Bid and Bax in particular. Finally, completion of the research will
facilitate the design of genetic and pharmacological strategies to ameliorate ischemic renal failure by targeting
Bid, Bax and their interaction.
StatusNot started

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