Role of Collecting Duct Chloride Transporters in Volume Regulation

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DESCRIPTION (provided by applicant): The balance between salt excretion and absorption in the kidney tubules is a major determinant of vascular volume homeostasis and systemic blood pressure. The kidney collecting duct plays a major role in the fine tuning of the final urine by regulating the transport of solutes, acid base molecules and fluid via distinct transporters in specialized cells. The absorption or secretion of chloride in the collecting duct constitutes a major component of systemic salt homeostasis. Chloride is absorbed in non A-intercalated cells, predominantly via pendrin (Slc26a4), however, very little is known about chloride secretion in the collecting duct and the molecule(s) mediating this process. We provide evidence demonstrating that Slc26a9 (PAT4), which can function as a chloride channel, is localized on the apical membrane of principal cells in the collecting duct. We further report that mice with genetic deletion of Slc26a9 display reduced ability to excrete chloride when subjected to water deprivation. These results strongly suggest that Slc26a9 plays an important role in chloride excretion by functioning as an apical chloride channel in the collecting duct. Further, we observe that Slc26a9 mice display elevated systemic blood pressure, which is aggravated with high salt intake, a phenotype likely related to their reduced ability to secret chloride. We provide evidence demonstrating that pendrin (Slc26a4) plays a major role in compensatory chloride absorption in the collecting duct in response to increased delivery of salt to the distal nephron caused by diuretics. Lastly and continuing with the proposed studies in our existing Merit Review award, we report the generation of collecting duct specific AE1 null mice. Both AE1 and Slc26a7 (PAT2) are Cl-/HCO3- exchangers expressed on the basolateral membrane of A-intercalated cells and play an important role in acid secretion and bicarbonate absorption in the outer medullary collecting duct. We hypothesize that Slc26a9 (PAT4) plays a major role in vascular volume homeostasis by regulating renal chloride secretion in the collecting duct. As such, we hypothesize that the downregulation or inhibition of Slc26a9 may play an important role in the pathogenesis of salt sensitive hypertension. We hypothesize that pendrin (Slc26a4) plays an important role in compensatory salt absorption in the collecting duct in response to diuretic therapy. As such, we hypothesize that pendrin can confer resistance to or blunt the effect of loop or DCT diuretics (furosemide or thiazide derivatives) by increasing the absorption of salt delivered to the distal nephron. Lastly, we hypothesize that the activation of Cl-/HCO3- exchangers PAT2 or AE1 by physiologic maneuvers can mitigate the severity of distal renal tubular acidosis in AE1 or PAT2 null mice, respectively. Ascertaining the role of collecting duct chloride transporters should shed new light on the pathophysiology of several disorders resulting from enhanced salt absorption or excretion, acid base disorders and blood pressure dysregulation originating from distal nephron. They will further provide novel therapeutic insights in patients with diuretic resistance, salt sensitive hypertension and altered acid base homeostasis.