The paradigm has long held that the epithelial Na channel ENaC, in conjunction with paracellular Cl- absorption, is the major path for salt absorption in the collecting duct whereas NCC is the main salt absorbing transporter in the DCT. Studies over the last decade have identified several new players in transcellular chloride and/or sodium reabsorption in the collecting duct (CD), including the Cl-/HCO3- exchanger Slc26a4 (pendrin), the Na+- dependent Cl-/HCO3- exchanger Slc4a8 (NDCBE), and the chloride transporter/channel Slc26a11 (KBAT). Unlike mice with single deletion of NCC or pendrin, simultaneous deletion of pendrin and NCC causes sharp increases in salt excretion, pointing to cross compensation between NCC and pendrin and their crucial role in salt absorption. No transcellular chloride-absorbing pathway has been identified in medullary collecting duct. New studies from our laboratory demonstrate that Slc26a11 (KBAT) is expressed on the apical membrane of A- intercalated cells in CCD, OMCD and iIMCD and plays an important role in salt absorption. The schematic diagrams in Figs. 2, 6 and 7 depict the interaction of KBAT and pendrin with other ion transporters in the CCD. Preliminary results: KBAT expression is enhanced in response to furosemide treatment, NCC or pendrin deletion, and salt loading, raising the possibility that KBAT plays an important role in salt absorption in the setting of enhanced delivery of salt to the collecting duct. We have generated mice with kidney specific [(or global)] ablation of KBAT, which show significant salt wasting in response to the loop diuretics or following increased dietary salt intake. Hypothesis: We hypothesize that KBAT plays an important role in salt absorption in the entire collecting duct, cross compensates for NCC or pendrin inactivation and/or inhibition and mitigates the salt loss in response to enhanced salt delivery to the collecting duct. As a result, we predict that KBAT inactivation will result in excess salt wasting consequent to diuretic therapy, in the setting of NCC or pendrin inhibition/inactivation, and in response to salt loading, the latter reflecting a unique role for this transporter in salt absorption in salt replete states [and in salt/DOCA hypertension]. Lastly, we hypothesize that KBAT and pendrin work in tandem with ENaC and/or NDCBE [(the global KO of the latter has been generated in our lab)] to reabsorb salt in CD. Innovation: The proposed research will elucidate the role of KBAT and pendrin as major players in salt reabsorption in distal nephron and as novel targets for diuretic therapy. Approach: A combination of genetically engineered mouse models, metabolic balance studies, tubule microperfusion, systemic blood pressure measurement by telemetry and molecular studies will be employed to ascertain the role of KBAT and pendrin in salt reabsorption and identify their sodium absorbing partners in the collecting duct. Insight into the role of KBAT and pendrin will significantly enhance our understanding of the role of these transporters in salt reabsorption and blood pressure homeostasis. The proposed studies will further lay the ground for development of inhibitors of KBAT and pendrin as novel diuretics in fluid overloaded states.

A large number of our veterans are admitted to the hospital with altered systemic blood pressure or excess fluid. The distal nephron of the kidney plays a major role in vascular volume homeostasis and blood pressure regulation by regulating the absorption of salt via specialized molecules. We have identified two transport proteins in the kidney collecting duct that play important roles in salt absorption, regulation of blood pressure and vascular volume homeostasis. We believe that the examination of the role of these transporters and their interaction with other known transport proteins through the use of genetically engineered mouse models should provide novel insight into the pathogenesis of various diseases associated with increased blood pressure or fluid overload. Further, the information gathered can be eventually used to design therapeutic maneuvers aimed at rectifying elevated blood pressure or excess fluid in patients with hypertension, congestive heart failure or fluid overload.