Type B intercalated cells secrete HCO3- and absorb Cl- across the apical plasma membrane through the action of the Cl-/HCO3- exchanger, pendrin. Pendrin-mediated Cl-/HCO3- exchange reduces arterial pH and HCO3- concentration, thereby attenuating a metabolic alkalosis. Pendrin-mediated Cl- absorption also contributes to the vascular volume expansion observed in rodent models of NaCl-sensitive hypertension, such as following a high NaCl diet and aldosterone analogues (deoxycorticosterone pivalate, DOCP). We have observed that the hypertension expected with DOCP administration and a high NaCl diet is not observed in mice with genetic disruption of the gene encoding pendrin (Slc26a4). The absence of aldosterone-induced hypertension in Slc26a4 null mice occurs most likely not only from the absence of pendrin-mediated Cl- uptake but also from the reduced epithelial Na+ channel (ENaC) expression observed in the kidneys of these mutant mice. However, pendrin and ENaC are regulated through both aldosterone-dependent and -independent mechanisms. Our laboratory and others have shown that angiotensin II stimulates Na+ and Cl- absorption in the cortical collecting duct (CCD) when perfused in vitro through synergy between pendrin and ENaC. How angiotensin II stimulates pendrin and ENaC expression and function and how pendrin and ENaC interact to promote NaCl absorption is the subject of the present proposal. The aims of this proposal are the following: 1) to determine the mechanism whereby angiotensin II stimulates pendrin-mediated Cl-/HCO3- exchange in vitro and to determine how ENaC and pendrin interact following angiotensin II to increase NaCl absorption, 2) to determine the mechanism of the long-term regulation of pendrin by angiotensin II in vivo and how pendrin modulates ENaC expression in vivo and 3) to determine the mechanism for the interdependency of pendrin and ENaC expression. To accomplish these objectives wild type and genetically modified mice, such as Slc26a4 (-/-), total and cell-specific AT1a (-/-), tissue-specific ENaC (-/-) and mouse models of Liddle's Syndrome, will be studied using quantitative real time PCR, light microscopic immunohistochemistry, immunogold cytochemistry and immunoblots. Transport will be studied in mouse renal tubules perfused in vitro and in cultured mouse principal cells. Whole animal studies will be employed further in balance studies and measurements of blood pressure and GFR.7. Project Narrative: Our laboratory has observed that a protein called pendrin mediates absorption of chloride by the kidney, which increases blood pressure. In addition, pendrin also regulates absorption of sodium by the kidney by changing the amount of a protein that transports sodium within the kidney (i.e. the epithelial sodium channel, ENaC). This proposal will explore how pendrin controls absorption of sodium and chloride by the kidney.
NIH ExPorter
NIH ExPorter