Lysine Acetylation and the Regulation of Vasopressin/Aquaporin System in the Principal Cell

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SUMMARY Dysregulation of arginine vasopressin (AVP) and water channels, called aquaporins (AQPs), can lead to a variety of clinically-significant water-electrolyte problems, ranging from severe dehydration to low plasma sodium. The actions of AVP in the kidney are mediated via the AVP receptor 2 (AVPR2) predominantly on the kidney principal cell. The AVP-sensitive water channels, AQP2 and AQP3, promote water reabsorption to prevent dehydration. In doing so these water channels function to concentrate the urine. Based on our compelling preliminary data, this proposal focuses on the first reported modification of AQP3, lysine 282 acetylation, in the regulation of substrate permeability. Lysine acetylation is also important for gene expression and it is regulated via acetyltransferases and deacetylases (HDACs) enzymes. We recently performed a systemic review and metanalysis and determined that chronic HDAC inhibitor use, as occurs in the treatment of cancers, results in a significant >2 odds ratio of experiencing fluid-electrolyte disorders in humans. Thus, determining the functional significance of lysine acetylation in the kidney is critically important both from a physiological perspective and in understanding the clinical impact of HDAC inhibition on water-electrolyte balance. Together, our compelling preliminary data have led us to formulate the overarching hypothesis that regulation of the kidney AVPR2/AQP axis by lysine acetylation is critical in regulating urinary concentrating ability and fluid balance. This will be tested by the following two aims: Aim 1: To test the hypothesis that lysine acetylation of AQP3 increases substrate flux in the principal cell promoting urine concentration. Aim 2: To test the hypothesis that HDAC1 and HDAC2 regulate the transcription of the AVPR2/AQP axis in the principal cell. We will combine unbiased, system biology approaches with cell to whole animal experiments to close key gaps in our understanding of concentrating mechanisms in the kidney and may reveal new therapeutic avenues to treat fluid-electrolyte disorders.