No Zoom Required: Meeting at the β-Intercalated Cells
Authors: Wie-Yin Lin, Shmuel Muallem
Journal: Journal of the American Society of Nephrology (2020)

Acid-base balance is vital for life and is maintained primarily by the kidney, which excretes excess acid or base ingested in the diet or generated by metabolism. Transport mechanisms along the nephron are dedicated to the bulk of acid or base excretion, with final tuning performed by the connecting tubule and the collecting duct.1 The connecting tubule and the cortical connecting duct (CCD) have three main cells: the principal cells, the α intercalated cells (ICs), and the βICs.2 The principal cells fine-tune Na+ absorption by the use of the luminal epithelial Na+ channel, the αICs use the V-type H+ pump and a K+/H+ ATPase isoform to secrete acid, and the βICs use the luminal Cl−/HCO3− exchanger pendrin to absorb Cl− and secrete HCO3−.1,2 The βICs also express the cAMP-activated Cl− channel Cystic Fibrosis Transmembrane conducrance Regulator (CFTR) that appears to regulate pendrin expression.2 The three cell types communicate to maintain balanced systemic acid-base homeostasis in response to any perturbance, such as the postprandial alkaline tide. The alkaline tide occurs in response to luminal gastric acid secretion by the parietal cells that is accompanied by basolateral HCO3− secretion into the circulation. The postprandial alkaline tide causes secretion of the hormone secretin, which stimulates pancreatic HCO3− secretion into the gut3 and at the same time stimulates renal HCO3− excretion.4 In this issue of JASN, the Leipziger laboratory5 determines the molecular mechanism by which secretin regulates renal HCO3− excretion. Berg et al.5 began their quest by noting that the βICs express CFTR, pendrin (solute carrier family 26, member 4 [Slc26a4]), and secretin receptors. They also recognized that patients with mutations in pendrin or with cystic fibrosis (CF) often suffer from metabolic alkalosis. They hypothesized that pendrin, a member of the SLC26 Cl−/HCO3− exchangers and Cl− channels family,3 and CFTR might respond to secretin to mediate HCO3− excretion by βICs. Indeed, βICs from pendrin−/− mice and from CFTR−/− mice showed markedly reduced secretin- and cAMP-stimulated luminal Cl−/HCO3− exchange activity. Moreover, the two knockout mouse lines failed to secret HCO3− and form alkaline urine in response to secretin stimulation, and CFTR−/− mice failed to increase urine HCO3− excretion in response to acute metabolic alkalosis.5 These findings have led to the conclusion that activation of CFTR by secretin-stimulated Protein Kinase A (PKA) phosphorylation activates pendrin to mediate HCO3− secretion by the CCD in βICs. Similarly, recent studies in airway surface epithelia have shown mutual activation of pendrin and CFTR by cAMP/PKA stimulation.6 Berg et al.5 also confirm another effect of CFTR expression in βICs, which is the stabilization of pendrin expression.2 An important aspect of the study by Berg et al.5 is the demonstration of the clinical relevance of the regulation of pendrin by CFTR. Patients with CF with the ΔF/ΔF mutation have reduced urine HCO3− concentration and a markedly reduced ability to excrete HCO3− in response to an oral HCO3− load. Moreover, treating patients with a combination of CFTR corrector and activator (Orkambi) for 4 weeks partially restores urinary HCO3− excretion.5 Together, the findings of Berg et al. establish the role of CFTR in controlling renal HCO3− excretion and metabolic alkalosis, and provide, for the first time, a molecular mechanism explaining the role of secretin in renal physiology. The findings of Berg et al.5 raise several important questions such as how does the cAMP/PKA pathway mediate the mutual regulation of pendrin and CFTR, and why is an active CFTR needed for the activation of pendrin? Other queries include whether the regulation of pendrin by CFTR affects other renal roles of pendrin, and does CFTR have other roles in the kidney besides the regulation of pendrin? If so, would other roles of pendrin and CFTR in the kidney be affected by the CFTR-correcting drugs, and can the urine test used by Berg et al.5 be used as another diagnostic test for CF? Some information is available to address parts of these questions. Pendrin is not the only SLC26 transporter that is regulated by CFTR. In fact, all members of the SLC26 transporter family examined to date are regulated by CFTR.3 This is illustrated in Figure 1. The interaction is mediated by the CFTR R domain and the Sulphate Transporter and AntiSigma factor antagonist domain of the SLC26 transporters. The interaction requires phosphorylation of the R domain by PKA.7 In the resting state, the R domain is occluded between the two cytoplasmic sectors of CFTR, preventing interaction of the two nucleotide binding domains. Phosphorylation of the R domain by PKA causes outward swinging of the R domain and interaction of the nucleotide binding domains,8 and allows interaction of the R domain with the Sulphate Transporter and AntiSigma factor antagonist domain of SLC26 transporters (Figure 1). The interaction stabilizes expression of the two proteins and results in their mutual activation.7 This mechanism accounts for the stabilization of pendrin expression and its activation by the active form of CFTR.5Figure 1.: Interaction with and regulation of the SLC26 transporters by CFTR. The structures of the unphosphorylated CFTR (5UAK) and the phosphorylated CFTR (6MSM) were taken from Zhang et al.,8 and of Slc26a9 (6RTF) from Walter et al. 10 In the inactive state, the R domain of CFTR prevents the interaction of the NBDs and is not available for interaction with other proteins. The basal activity of the SLC26 transporters, including pendrin, is low with the two STAS domains of the two monomers interacting with each other. An increase in cAMP and activation of PKA phosphorylates the R domain, resulting in the swinging of the R domain and its interaction with the STAS domain, which can facilitate and stabilize the interaction of the nucleotide binding clefts to activate CFTR. Interaction of the R domain with the STAS domain stabilizes expression and activates the SLC26 transporters. NBD, nucleotide binding domain; TMD, transmembrane domain.Pendrin has several effects associated with HCO3− excretion and Cl− absorption. Pendrin regulates BP by mediating NaCl absorption and regulating the activity of the luminal epithelial Na+ channel in principal cells and I− transport in the thyroid. Pendrin is expressed in the adrenal medulla where it modulates the release of catecholamines.2 The role of pendrin activation by CFTR in these contexts is unknown. The renal expression level of pendrin is markedly affected by the systemic metabolic state, increasing in alkalosis and decreasing in acidosis.2 Whether the expression of CFTR in βICs changes in parallel is not known. CFTR is expressed at the CCD but also in other segments of the nephron9 together with other SLC26 transporters, such as the 1Cl−/2HCO3− and Cl−/oxalate− exchanger Slc26a6 and the SO42−/OH−/Cl− exchanger Slc26a2.3 Regulation of renal Slc26a6 by CFTR may therefore affect oxalate homeostasis and the formation of calcium oxalate kidney stones. Further studies examining these questions should improve our understanding of the response of the kidney to metabolic perturbation, and the physiologic role of the mutual regulation of CFTR and the SLC26 transporters. Disclosures All authors have nothing to disclose. Funding W-Y Lin and S. Muallem are supported by an intramural National Institutes of Health grant from the National Institute of Dental and Craniofacial Research (DE000735-09).