The role of collecting duct chloride transporters in salt absorption and blood pressure homeostasis

该范例长期以来一直认为上皮Na通道ENaC与细胞旁Cl-吸收结合， NCC是集水管中主要的吸盐通道，而NCC是集水管中主要的吸盐转运体。 DCT。过去十年的研究已经确定了几个跨细胞氯和/或钠的新参与者 收集管（CD）中的重吸收，包括Cl-/HCO 3-交换器Slc 26 a4（pendrin），Na+- 依赖性Cl-/HCO 3-交换器Slc 4a 8（NDCBE）和氯转运蛋白/通道Slc 26 a11（KBAT）。 与单一缺失NCC或pendrin的小鼠不同，同时缺失pendrin和NCC导致尖锐的 盐排泄增加，指出NCC和pendrin之间的交叉补偿及其在 盐吸收在髓质集合管中没有发现跨细胞的氯离子吸收途径。 我们实验室的新研究表明，Slc 26 a11（KBAT）表达于A- 在CCD、OMCD和iIMCD中的插入细胞，在盐吸收中起重要作用。逻辑示意图 图中的图表图2、6和7描述了KBAT和pendrin与CCD中其他离子转运蛋白的相互作用。 初步结果：KBAT表达增强，对呋塞米治疗，NCC或pendrin的反应 删除和盐加载，提高了KBAT在盐吸收中起重要作用的可能性。 增强了盐向集合管的输送。我们已经产生了肾脏特异性[（或全球）] KBAT消融，显示对袢利尿剂的反应或增加后的显着盐浪费 食盐摄入量假设：我们假设KBAT在整个盐吸收中起着重要作用。 收集管，交叉补偿NCC或pendrin失活和/或抑制，并减轻盐损失 以响应向收集管的盐输送的增强。因此，我们预测，KBAT失活将 在NCC或pendrin的情况下，利尿剂治疗导致过量的盐消耗 抑制/失活，并响应盐负荷，后者反映了这种转运蛋白在盐中的独特作用 盐饱状态下的吸收[和盐/DOCA高血压]。最后，我们假设KBAT和pendrin 与ENaC和/或NDCBE [（后者的全局KO已在我们的实验室中生成）]协同工作以重吸收 盐在CD创新：拟议的研究将阐明KBAT和pendrin作为 盐重吸收在远端肾单位和利尿剂治疗的新目标。方法：结合 基因工程小鼠模型，代谢平衡研究，肾小管微灌注，全身血液 通过遥测和分子研究进行的压力测量将用于确定KBAT的作用， pendrin在盐重吸收中的作用，并确定它们在集合管中的钠吸收伙伴。洞察 KBAT和pendrin的作用将显著增强我们对这些转运蛋白在盐中作用的理解。 重吸收和血压稳态。建议的研究将进一步奠定发展基础 KBAT和pendrin的抑制剂作为液体超负荷状态下的新型利尿剂。

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.