Abstract
The prevailing view is that the ClC-Ka chloride channel (mouse Clc-k1) functions in the thin ascending limb to control urine concentration, whereas the ClC-Kb channel (mouse Clc-k2) functions in the thick ascending limb (TAL) to control salt reabsorption. Mutations of ClC-Kb cause classic Bartter syndrome, characterized by renal salt wasting, with perinatal to adolescent onset. We studied the roles of Clc-k channels in perinatal mouse kidneys using constitutive or inducible kidney-specific gene ablation and 2D and advanced 3D imaging of optically cleared kidneys. We show that Clc-k1 and Clc-k2 were broadly expressed and colocalized in perinatal kidneys. Deletion of Clc-k1 and Clc-k2 revealed that both participated in NKCC2- and NCC-mediated NaCl reabsorption in neonatal kidneys. Embryonic deletion of Clc-k2 caused tubular injury and impaired renal medulla and TAL development. Inducible deletion of Clc-k2 beginning after medulla maturation produced mild salt wasting resulting from reduced NCC activity. Thus, both Clc-k1 and Clc-k2 contributed to salt reabsorption in TAL and distal convoluted tubule (DCT) in neonates, potentially explaining the less-severe phenotypes in classic Bartter syndrome. As opposed to the current understanding that salt wasting in adult patients with Bartter syndrome is due to Clc-k2 deficiency in adult TAL, our results suggest that it originates mainly from defects occurring in the medulla and TAL during development.
Highlights
Chloride ion (Cl–) is the major anion providing charge balance to sodium ion (Na+)
The ClC-type chloride channels ClC-Ka and ClC-Kb are expressed in the ascending limbs and distal nephrons of human kidneys, and human mutations in these channels have been associated with disorders of salt and water homeostasis [1,2,3,4]
Antenatal Bartter syndrome is caused by mutations in either the sodium-potassium-chloride cotransporter type 2 (NKCC2) or the renal outer medullary potassium (ROMK) channel, both of which are critical for NaCl entry through the apical membrane of thick ascending limb (TAL)
Summary
Chloride ion (Cl–) is the major anion providing charge balance to sodium ion (Na+). Cl– transport across the renal tubule is vital to renal NaCl reabsorption. The ClC-type chloride channels ClC-Ka and ClC-Kb are expressed in the ascending limbs and distal nephrons of human kidneys, and human mutations in these channels have been associated with disorders of salt and water homeostasis [1,2,3,4]. A hereditary renal tubulopathy affecting NaCl reabsorption in the thick ascending limb (TAL) of the loop of Henle, is divided into antenatal and classic types based on the severity of perinatal presentation. Antenatal Bartter syndrome is caused by mutations in either the sodium-potassium-chloride cotransporter type 2 (NKCC2) or the renal outer medullary potassium (ROMK) channel, both of which are critical for NaCl entry through the apical membrane of TAL. Classic Bartter syndrome, caused by loss-of-function mutations in ClC-Kb in the basolateral membrane of TAL, has more-variable phenotypes, ranging from perinatal disease to adolescent-onset salt wasting [5]. A recent report suggests that genotype accounts for phenotype variabilities [6, 7], but this hypothesis does not explain the phenotypic variability observed commonly among siblings carrying the same ClC-Kb mutation [8]
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