Laboratory of Integrated Kidney Function

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Summary The goal of the Integrated Kidney Function Core is to provide a wide range of services and to support the research projects of each PI of the Program Project Group. The progress in molecular genetics has greatly broadened our understanding of renal physiology and pathophysiology. Genetically altered animals provide elegant models to examine the contributions of individual proteins to the maintenance of normal function and pathophysiology of disease. Genetically modified animals are widely used as a powerful tools with which to characterize the physiological or pathphysiological roles of specific proteins, channels, pumps or transporters. These studies are important to understand the mechanisms of diseases and to look for novel targets for the treatment of clinical diseases. However, due to technical difficulties the characterization of knockout and transgenic mouse models has been largely limited to blood and urine electrolyte measurements. We are able to examine complete renal functions in vitro and in vivo, from whole animals to single nephrons, by renal clearance analysis and by microperfusion of renal tubules from rat or mouse. Using these methods, we are able to measure salt, water and acid-base transport as well as protein absorption in the kidney. Comparisons between normal vs. genetically modified animals in which a specific protein, channel or transporter is altered will provide invaluable information on physiology, pathophysiology and adaptation to diseases. The Integrated Kidney Function Core has played a uniquely important role in renal physiology research by supporting many research projects in the Program Project Grant. This core is staffed by well trained people who are skilled in all techniques needed to assess renal transport functions from the whole animal to the single nephron levels. Services and collaborations provided from this core lab provide each PI in the program project with tools that will allow them to connect their cellular and molecular observations to physiological and pathophysiological processes. To facilitate the overall goal of the Program Project, we plan to provide the following specific services as proposed in the projects: 1. To examine and compare the phenotypes of Na+, K+ Ca2+ and Mg2+ transport observed in ROMK and WNK4 (PHAII) mutant mice to those obtained from KLHL3 and CUL3 mutant mice (Project #1); 2. To measure both net Cl- transport and cellular Cl- concentrations under low and high tubular flow rates to study the physiological role of NKCC1 in the regulation of collecting tubule K+ transport (Project # 2); 3. To examine physiological inhibition (By PTH, dopamine) or stimulation (by Ang II, glucocorticoid) of NHE3 activity in response to NHE3 phosphorylation at sites that correlate with increased or reduced NHE3 activities (Project #3); and 4. To study electrolyte transport and the effects of ischemic injury in animal models manifesting altered AMPK expression (Project #4).