BIOLOGY OF COMPENSATORY ADAPTATION IN COLLECTING TUBULE

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The proposed project examines the signals, nature, and mechanisms of the functional and structural adaptation that occurs in the renal collecting tubule after reduction of renal mass. Since the collecting tubule is the final regulator of urinary excretion of water and solutes, the adaptation of this segment obviously is critical for the maintenance of total body homeostasis. Preliminary studies have shown that intrinsic adaptive changes in the collecting tubule are retained when studied in vitro. Based on preliminary studies, three main hypothesis have been formulated to address the adaptation process: 1) Adaptation of sodium transport and hypertrophy in the cortical collecting tubule (CTT) depend on increased luminal delivery of sodium and/or increased apical sodium permeability, and require the presence of basal mineralocorticoid levels; 2) There is a generalized defect in several cAMP-mediated hormonal actions in the collecting tubule; 3) Growth factors are important in the development of compensatory adaptation; their effect is maintained as altered tubular transport rates. These hypotheses will be tested in vitro in isolated collecting transport rates. These hypotheses will be tested in vitro in isolated collecting tubules from remnant kidneys with several probes including: 1) morphometric studies, 2) biochemical assays (Na-K-ATPase and adenylate cyclase), and 3) functional transport parameters (ion transport, conductivities, intracellular pH measurements). A variety of dietary, in vivo and in vitro pharmacologic, and other maneuvers will be utilized to interfere with the putative mechanisms operative in compensatory adaptation and thus identify the specific role of each. For instance, adaptation in sodium transport will be studied under conditions where each one of the proposed key factors is separately eliminated. Similarly, pharmacologic tools will be used to separately probe several of the steps involved in hormone-cAMP mediated effect in three separate systems (ADH-water permeability in cortical collecting tubule, beta-adrenergic stimulation of bicarbonate secretion in cortical collecting tubule, and cAMP-stimulated bicarbonate absorption in medullary collecting tubule). Effect of growth factors on several cellular functions will also be tested and correlated with the development of compensatory adaptation.