Intercalated Cell ClC-K2 Channel Contributes to Systemic Cl^- Balance and Acid-Base Homeostasis

Maintaining systemic Cl^- homeostasis plays a critical yet underappreciated role in setting the baseline and salt sensitivity of blood pressure. ClC-K2 Cl^--permeable channel is localized on the basolateral membrane of the distal nephron segments. Impaired NaCl reabsorption in the thick ascending limb and distal convoluted tubule has been proposed as the underlying cause of polyuria and hypotension in patients with the Bartter's syndrome type 3 due to loss-of-function of the channel. However, the relevance of ClC-K2 in the collecting duct intercalated cells (ICs) for renal function and Cl^- homeostasis remains obscure. Here, we compared the systemic manifestations and examined signaling components in ClC-K2^fl/fl Pax8 (lacking ClC-K2 in renal nephron) and ClC-K2^fl/fl B1 ATPase (lacking ClC-K2 in ICs) mice. ClC-K2^fl/fl Pax8 mice exhibited hypotension, reduced glomerular filtration rate, urinary NaCl wasting, and metabolic alkalosis with hypokalemia, thereby recapitulating the phenotype of Bartter's syndrome. While ClC-K2 deletion in ICs did not affect urinary volume and baseline blood pressure, ClC-K2^fl/fl B1 ATPase mice developed moderate hypotension in response to dietary Cl^- deficiency. Decreased expression and impaired apical translocation of pendrin (Slc26A4) were causative for the augmented urinary Cl^- excretion. Furthermore, ClC-K2 deletion in ICs interfered with the development of Angiotensin II-dependent hypertension. The reduced pendrin function, along with a compensatory upregulation of the epithelial Na⁺ channel, caused hypokalemic metabolic alkalosis in ClC-K2^fl/fl B1 ATPase mice. In summary, we show that ClC-K2 activity in ICs of the collecting duct plays physiologically relevant roles in the regulation of systemic Cl^- balance and acid-base homeostasis.