Mechanisms of Disease: the kidney-specific chloride channels ClCKA and ClCKB, the Barttin subunit, and their clinical relevance

Abstract

Rodent ClC-K1 and ClC-K2, and their respective human orthologs ClCKA and ClCKB, are chloride channels specific to the kidney (and inner ear); Barttin is their functionally important subunit. ClC-K1 is predominantly localized to the thin ascending limb of the loop of Henle. ClC-K2 is expressed more broadly in the distal nephron; expression levels are highest along the thick ascending limb of the loop of Henle and distal convoluted tubule. Expression of ClC-K1 is upregulated by dehydration and downregulated by the diuretic furosemide, whereas expression of ClC-K2 is upregulated by furosemide and downregulated by high salt levels. ClCKA is important for maintenance of the corticomedullary osmotic gradient and the kidney's capacity to concentrate urine. If its ortholog, ClC-K1, is nonfunctional in mice, renal diabetes insipidus develops. ClCKB is a key determinant of tubular reabsorption of chloride and electrolytes along the distal tubule. A severe salt-losing tubulopathy (Bartter syndrome type III) develops if ClCKB is nonfunctional, whereas a common genetic variant of the CLCNKB gene that leads to increased activity of ClCKB results in salt-dependent hypertension. Disruption of the gene encoding Barttin, BSND, results in a 'double knockout' of the functions of both ClCKA and ClCKB, manifesting as Bartter syndrome type IV with sensorineural deafness and an especially severe salt-losing phenotype.

PPARγ Agonists, Modulation of Ion Transporters, and Fluid Retention

“…14 Conversely, a gain-of-function genetic variant of ClC-Kb is associated with salt-sensitive increases in BP, predisposing people with the polymorphism to hypertension. 14 This link between BP regulation and Cl Ϫ transport substantiates a heretofore unappreciated role for anions in salt and fluid homeostasis.…”

The renal channelopathies

“…CLCNKB mutations reflect the nephron distribution of ClC-Kb, with a later-onset, milder Bartter phenotype and features of Gitelman syndrome also present (including a tendency to develop hypomagnesaemia). 64 A hallmark of the antenatal Bartter syndromes is hypercalciuria (with resultant nephrocalcinosis), but urinary Ca 2þ excretion is normal in those with CLCNKB mutations, indicating some preservation of TAL function, likely through basolateral ClC-Ka activity.…”

“…Changes in intracellular volume, inhibition of NKCC2 and local effects of the renin-angiotensin system are thought to regulate ClC-Ka function; a high salt diet and direct effects of furosemide regulate ClC-Kb. 64 Expression of functional channels (ClC-Ka, -Kb, -K2, but not -K1) in Xenopus and epithelial cell culture requires the presence of an additional subunit Barttin, a small protein with 2 transmembrane domains that is necessary for membrane insertion and stability, plus anion conductance. 41,65,66 Mutations in BSND, encoding Barttin, result in perinatal Bartter syndrome with sensorineural deafness.…”

A unique finding of normal aldosterone level in Bartter’s syndrome

“…Bartter's syndrome type 2 is due to a mutation in ROMK gene (renal outer medullary potassium channel gene) that encodes ATP sensitive potassium channels disrupting the regulation of potassium in the tubular lumen (9). Bartter syndrome type 3 is a salt losing tubulopathy due to a mutation on chromosome 1 that encodes for Barttin and renders only kidney-specific chloride channel B (ClCKB) non-functional (10 (15,17). Rofecoxib can also be administered in patients, refractory to indomethacin treatment (18).…”