Acute kidney injury (AKI) is a common event associated with high morbidity and mortality. Ischemia is a major cause of AKI. TRPM2, a member of the transient receptor potential- melastatin subfamily, is activated by oxidant stress, ADP-ribose, TNF and intracellular calcium, all of which are increased during kidney ischemia. We found that genetic or pharmacologic inhibition of TRPM2 dramatically reduces ischemic kidney injury. The mechanism involves, at least in part, a TRPM2-dependent increase in Rac1 activity resulting in increased NADPH oxidase activity and oxidant stress. Having identified important and novel roles for TRPM2, Rac1 and NADPH oxidase in ischemic kidney injury, we propose that these pathways may be targeted to prevent acute kidney injury. We will conduct a multifaceted exploration of the mechanisms by which TRPM2 promotes kidney injury. Our central hypothesis is that TRPM2 represents a pivotal target in AKI which integrates multiple injury signals to activate oxidant production and cell death pathways. This hypothesis is based on our preliminary data which clearly indicate that inhibition of TRPM2 or Rac1decrease AKI, oxidant stress and apoptosis. Our approach will employ both in vivo and in vitro models in pursuing an integrated analysis of TRPM2-dependent pathways active in AKI. We will test our hypothesis and achieve the objective of this application by pursuing the following specific aims:
Aim 1 : Determine the sites of TRPM2 expression which are responsible for kidney injury.
Aim 2 : Determine the mechanism and functional significance of TRPM2-dependent Rac1 activation in AKI.
Aim 3 : Determine the role and regulation of NADPH oxidase in ischemic AKI.
Aim 4 : Develop therapeutic interventions to reduce AKI and prevent the AKI-CKD transition. Successful completion of these aims will advance the field by elucidating the mechanistic connections between ion channel activation and subsequent kidney injury while identifying tractable therapeutic targets.
The proposed studies will elucidate the key role of TRPM2, Rac1 and NADPH oxidase in the pathogenesis of ischemic acute kidney injury. These results will be relevant because they are expected to lead to clinical trials to test the efficacy of inhibitors of these pathways for the prevention or treatment of acute renal injury.
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