Regulation of mRNA stability in Kidney epithelia

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DESCRIPTION (provided by applicant): Project summary: Ischemic injury is at the heart of approximately 50% of all cases of acute renal failure. One hallmark of ischemia is a severe drop in cellular ATP levels, which promotes numerous changes in cellular functions, including broad suppression of transcriptional and translational activity. To survive this consequence of energy depletion, cells must maintain a pool of mRNA transcripts that encode proteins involved in critical cellular processes. Investigation into the role of the RNA-stabilizing protein HuR in an in vitro model of renal ischemic injury demonstrated that it is required for maintaining appropriate expression of select mRNAs during cellular ATP depletion. HuR, which may bind hundreds to thousands of distinct mRNA transcripts, shuttles from the nucleus to the cytoplasm during ischemic stress, where it is capable of preventing degradation of these mRNAs. Further, ATP depletion triggers stress-induced changes in translation of HuR, while recovery of ATP levels triggers new HuR mRNA transcription. These data suggest that HuR may play a large role in promoting kidney cell survival during ischemic injury. Examination of HuR in injured kidney epithelia demonstrates tubule segment-specific regulation of HuR expression and distribution, potentially reflecting different responses to this type of stress. The goal of this project is to discern the mechanisms behind enhanced HuR expression triggered by ischemic injury, and to more precisely define tubule segment-specific regulation of this protein. Because HuR may play a role in stabilizing thousands of critical mRNAs, this work should provide important insight into a critical aspect of cell survival during ischemic stress. Relevance: Loss of blood flow to the kidney is a common cause of renal failure. Whether induced by disease, trauma, or transplantation, this circulatory problem results in cell death and loss of kidney function. The object of the proposed work is to identify some of the mechanisms that kidney cells use to protect themselves from this type of injury, in hopes of creating the ability to intervene in this process and promote cell survival.