The major objectives of this research project are to investigate the cellular and subcellular mechanisms responsible for the renal regulation of acid-base transport by the collecting duct and to trace the maturation of such transport processes back to the perinatal period. The proposed studies will focus on the two types of acid-base transporting cells identified in the collecting duct, the H+- and HCO3 ion-secreting intercalated (mitochondria-rich) cells. Identification and functional assay of individual cells in the isolated perfused rabbit collecting duct will be performed with recently developed fluorescence staining techniques, including those which probe for the presence of mitochondria, carbonic anhydrase activity, endocytosis/exocytosis and surface binding of lectins and permit measurement of cell pH. Net HCO3 ion transport will be measured by microcalorimetry. In order to identify the functional polarity of the two types of intercalated cells with respect to location of the H+-ATPase and Cl-HCO3 ion exchanger, the effect of luminal anion substitution for Cl- on HCO3 ion transport and intracellular pH will be studied. Because the high rate of H+ secretion characteristic of the medullary collecting tubule (MCT) may be due to conditioning by a relatively acidic medullary environment, regulation of HCO3 ion transport in this segment in response to chronic systemic alkalosis will be examined and the findings correlated with the numbers of H+- and HCO3 ion secreting intercalated cells present. The frequencies of H+- and HCO3 ion-secreting cells in cortical collecting tubules (CCT) obtained from animals subjected to chronic disturbances in metabolic and respiratory acid-base status and circulating mineralocorticoid levels will be compared with measurements of HCO3 ion transport to confirm the hypothesis that intercalated cells can be induced to reverse their functional polarity. The development of functional characteristics of the differentiated intercalated cell (carbonic anhydrase, cell pH, endocytosis/exocytosis, surface glycoproteins) will be traced back to the perinatal and embryonic periods in order to establish a fate map for the intercalated cell. As part of the investigation to determine when and how the cell becomes committed to secreting acid or base, the presence or absence of communication between intercalated and principal cells will be established in the immature CCT. The studies described in this application should allow us to better understand how metabolic and respiratory acid-base perturbations, mineralocorticoid excess, and genetic factors influence regulation and development of the intercalated cell.
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