Acute kidney injury (AKI) induced by renal ischemia-reperfusion continues to be a major kidney disease with unacceptably high mortality rates, increasing prevalence, and no effective therapies. Recent work has further implicated ischemic AKI in the development and progression of chronic kidney diseases. The goal of our research is to delineate the cellular and molecular basis of ischemic AKI and formulate preventive and therapeutic strategies. Using a conditional (renal proximal tubule specific) Dicer- knockout mouse model, we have recently demonstrated the first evidence for the involvement of microRNAs in ischemic AKI. Our microarray analysis has further identified 13 microRNA species that markedly change expression during renal ischemia-reperfusion. Despite these findings, it is unknown which microRNAs contribute significantly to ischemic AKI and how. Our preliminary studies have now verified the dramatic induction of miR-687 early during ischemic AKI. We have further suggested that miR-687 may target PTEN, a key regulator of cell viability, cell cycle, growth, and proliferation. At the upstream level, miR-687 may be subjected to transcriptional regulation by hypoxia-inducible factor, HIF. Based on these findings, we hypothesize that specific microRNA species play important roles in the pathogenesis of ischemic AKI. In these microRNAs, miR-687 is induced via HIF and regulates ischemic AKI by suppressing PTEN and promoting tubular cell survival and regeneration during kidney recovery and repair. We will test this hypothesis by three specific aims: 1) To characterize microRNA expression and determine the roles played by specific microRNAs in ischemic AKI;2) To identify HIF as an upstream transcription factor leading to miR-687 expression during renal ischemia-reperfusion;3) To identify PTEN as a downstream target of miR-687 and a regulator of ischemic AKI. Completion of this project will not only gain novel insights into the molecular regulation of AKI by microRNAs but will also unveil new therapeutic strategies. Targeting microRNAs and their regulatory pathways may lead to clinically applicable approaches for the prevention and treatment of AKI.
Acute kidney injury (AKI) induced by renal ischemia-reperfusion continues to be a major kidney disease with unacceptably high mortality rates (over 50%), increasing prevalence, and no effective therapies. The research of this application will not only unveil a new mechanism of ischemic AKI involving microRNAs and gain insights into the regulation but will also suggest novel therapeutic strategies. Targeting microRNAs and their regulatory pathways may lead to clinically applicable approaches for the prevention and treatment of AKI in the near future.
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