Common genetic variants and haplotypes in renal CLCNKA gene are associated to salt-sensitive hypertension

Abstract

Abnormal renal reabsorption of sodium (Na(+)) is likely to play a role in the pathogenesis of salt-sensitivity. In the kidney, chloride channels CLC-Ka (gene CLCNKA) and CLC-Kb (gene CLCNKB) and their subunit Barttin (gene BSND) have important effects on the control of Na(+) and water homeostasis. We investigated if single nucleotide polymorphisms (SNPs) or haplotypes within CLCNKA, CLCNKB and BSND loci affect salt-sensitivity in hypertensive subjects. Associations between blood pressure (BP) change after Na(+)-load and 15 SNPs spanning the length of CLCNKA and CLCNKB and six SNPs spanning the length of BSND were studied in 314 never treated essential hypertensives who underwent an i.v. infusion of saline (300 mm NaCl in 2 l H(2)O in 120 min). Four SNPs were significantly associated with BP change after Na-load. Rs848307 (P = 0.0026) and rs1739843 (P = 0.0023) map upstream the 5' of CLCNKA. Non-coding Rs1010069 (P = 0.0006) and non-synonymous rs1805152 (Thr447Ala; P = 0.0078) map within CLCNKA. Moreover, basal plasma renin activity and heart rate (measured before Na-load) were significantly lower in patients carrying the alleles associated with the larger mean BP increase after Na-load, indicating that such alleles are associated with chronic volume expansion. This study supports the candidacy of CLCNKA as a new susceptibility gene for salt-sensitivity.

Upregulation of apical sodium-chloride cotransporter and basolateral chloride channels is responsible for the maintenance of salt-sensitive hypertension

“…In addition, it has been recently shown that salt-sensitive hypertension may be associated with chloride channel polymorphism (2). Therefore, our observation of a significant increase in active channel density, but not of other channel biophysical characteristics, in DCT cells of MHS rats is well in agreement with the possibility of an increased transepithelial NaCl flux during the maintenance phase of hypertension.…”

Carboxyl-terminal Truncations of ClC-Kb Abolish Channel Activation by Barttin Via Modified Common Gating and Trafficking

“…CLCNKA mutations were associated with high blood pressure (10) or heart failure (11). In contrast, loss-of-function of hClC-Kb results in Bartter syn-drome type III, a genetic human disease condition characterized by hypokalemia, metabolic alkalosis, polyuria, polydipsia, and low blood pressure at increased levels of renin and aldosterone (9,12,13).…”

The renal channelopathies

“…[69][70][71] As mentioned, furosemide may exert some of its affect through an inhibitory action on ClC-K channels, and recently a number of novel compounds with direct ClCKa/b inhibition have been proposed as a future class of antihypertensive agents, following demonstration that they provoke a diuresis in rats. 72 …”