Physiologic role of collecting duct ciiliary proteins

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DESCRIPTION (provided by applicant): The purpose of current proposal is to study the physiologic role of collecting duct primary cilia in regulating renal electrolyte and water excretion and systemic blood pressure. Recent studies indicate that central cilia in renal tubular epithelial cells play an important role in renal pathology; many renal cystic disease gene products localize, at least in part, to the primary cilia, and mutations in these cystic components leads to cystic kidney disease. In contrast, the role of primary cilia in regulating renal tubular epithelial cells under normal physiologic conditions is unknown. A prevailing hypothesis is that primary cilia, by virtue of their apical location, transduce mechanical signals such as tubule fluid flow rate, that provide the cell with information about cell orientation. This information may be important in keeping tubule cells in a differentiated state. In addition, such mechanotransduction may help link tubule fluid flow rate with transepithelial electrolyte and water transport. Such a system may be particularly important in regulating collecting duct secretion of potassium and reabsorption of sodium and water. If so, then primary cilia in collecting duct may ultimately be vitally important in the control of systemic blood pressure. To test this possibility, the current proposal will have two major specific aims: 1) To generate mice with temporally-controlled collecting duct-specific knockout of genes likely to be involved in transducing flow-regulated cilia mechanosensation (pkdl or Tg737). Since conventional ciliary gene knockouts lead to cyst formation, the current study will acutely knockout target ciliary genes in adults. The goal is to develop animal models of ciliary gene knockout the permit physiologic analysis prior to the development of renal cysts. 2) To determine if deficiency of ciliary protein expression (polycystin-1 or polaris) in mice leads to altered systemic blood pressure and/or altered renal electrolyte and water excretion. Collecting duct electrolyte and water delivery will be acutely or chronically changed and the ability of the kidney to appropriately compensate renal salt and water excretion, as well as the blood pressure response, will be ascertained. These studies will begin to examine a fundamentally important yet largely unexplored area in renal physiology - the ability of the collecting duct to interact with its environment, through the primary cilia, to regulate renal salt and water excretion and systemic blood pressure. Such studies are designed to provide the groundwork for subsequent mechanistic analysis of ciliary regulation of renal tubule transport processes. Most importantly, this work may shed light on novel mechanisms involved in control of blood pressure and development of hypertension.