In Autosomal Dominant Polycystic Kidney Disease (PKD) there is progressive formation and enlargement of fluid-filled cysts in the kidney. Cyst enlargement and fluid accumulation result from net solute and fluid secretion from the reabsorption that prevails along most segments of the nephron normally. Taking advantage of the generation by Somlo and colleagues of mice and cell lines with genetically altered expression of polycystins, the overall design of this project is to test the hypothesis that deficient expression of polycystins alters the transport phenotype of renal tubular epithelial cells. To accomplish this goal we will pursue the following specific aims: 1. Characterize the renal physiological phenotype of mice generated by Project 1 with altered polycystin expression. As a function of age or time after induction of inactivation of the Pkd2 gene, measure blood pressure, GFR (inulin clearance), plasma electrolytes and acid-base parameters (Na+, K+, C1-, HC03-, Ph, pCO2), fractional excretion of electrolytes, urinary pH and ammonium excretion, and urinary concentration ability. 2. For mouse models in which fluid and electrolyte disturbance is detected before overt cyst formation, evaluate function of relevant nephron segments by microperfusion techniques. 3. By immunocytochemistry, identify sites of expression of major transporters that participate in NaCl reabsorption or secretion (Na+, K+, ATPase, Na+-H+ exchanger isoforms, Na+-K+-Cl-co-transporter isoforms, thiazide-sensitive co-transporter, EnaC subunits, ROMK, CFTR) in renal tubular cells and cyst lining in mouse PKD models. 4. Characterize transport phenotype of renal tubular cell lines generated by Project 1 that are genetically identical except for presence or absence of functional polycystin-2. Evaluate ion flux pathways and perform immunocytochemical localization of transporters that participate in NaCl reabsorption or secretion.
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