Altered potassium balance and aldosterone secretion in a mouse model of human congenital long QT syndrome

Abstract

The voltage-dependent K(+) channel responsible for the slowly activating delayed K(+) current I(Ks) is composed of pore-forming KCNQ1 and regulatory KCNE1 subunits, which are mutated in familial forms of cardiac long QT syndrome. Because KCNQ1 and KCNE1 genes also are expressed in epithelial tissues, such as the kidneys and the intestine, we have investigated the adaptation of KCNE1-deficient mice to different K(+) and Na(+) intakes. On a normal K(+) diet, homozygous kcne1(-/-) mice exhibit signs of chronic volume depletion associated with fecal Na(+) and K(+) wasting and have lower plasma K(+) concentration and higher levels of aldosterone than wild-type mice. Although plasma aldosterone can be suppressed by low K(+) diets or stimulated by low Na(+) diets, a high K(+) diet provokes a tremendous increase of plasma aldosterone levels in kcne1(-/-) mice as compared with wild-type mice (7.1-fold vs. 1.8-fold) despite lower plasma K(+) in kcne1(-/-) mice. This exacerbated aldosterone production in kcne1(-/-) mice is accompanied by an abnormally high plasma renin concentration, which could partly explain the hyperaldosteronism. In addition, we found that KCNE1 and KCNQ1 mRNAs are expressed in the zona glomerulosa of adrenal glands where I(Ks) may directly participate in the control of aldosterone production by plasma K(+). These results, which show that KCNE1 and I(Ks) are involved in K(+) homeostasis, might have important implications for patients with I(Ks)-related long QT syndrome, because hypokalemia is a well known risk factor for the occurrence of torsades de pointes ventricular arrhythmia.

Figure 1

Blood analyses in kcne1^−/− and wild-type mice at steady state on a normal diet. Plasma K⁺, Na⁺, Cl⁻, osmolality, and hematocrit were measured in blood collected from animals chronically fed a normal K⁺ (0.9%) and Na⁺ (0.3%) diet. In addition to the hypokalemia, kcne1^−/− mice present signs of dehydration as shown by the elevation in plasma osmolality and hematocrit and the increased plasma Na⁺ and Cl⁻ concentrations.

Figure 2

Plasma aldosterone and renin levels in kcne1^−/− and wild-type mice challenged with various K⁺ or Na⁺ diets. The dosages were performed on blood collected from animals maintained on a normal diet or fed high or low K⁺ diets or a low Na⁺ diet for 2 weeks. (A) The hyperaldosteronism in kcne1^−/− mice is blunted by low K⁺ or Na⁺ diets but strongly exacerbated by high K⁺ intake. (B) PRC is not different between kcne1^−/− and wild-type mice except on the high K⁺ diet, which does not decrease PRC in kcne1^−/− mice. PRC is expressed as the amount of angiotensin I formed per ml of plasma per h of incubation.

Figure 3

Fecal and urinary K⁺ and Na⁺ excretion in kcne1^−/− and wild-type mice challenged with various K⁺ diets. Twenty-four-hour urinary and fecal excretion were determined on animals fed high or low K⁺ diets for 2 weeks. (A) Compared with wild-type mice, kcne1^−/− mice lose K⁺ and Na⁺ in the feces for all K⁺ intakes. (B) Urinary K⁺ and Na⁺ excretion normalized to creatinine excretion are not different between kcne1^−/− and wild-type mice whatever the K⁺ intake.

Figure 4

Adaptation of fecal and urinary K⁺ excretion to varying K⁺ plasma levels and ion transport assessment in the colon of kcne1^−/− and wild-type mice. (A and B) Colon and renal functions were estimated by plotting mean values of plasma K⁺ levels and fecal or urinary 24-h K⁺ excretion reached by the mice on the various K⁺ diets. The overall adaptation of the kidneys is not affected in kcne1^−/− mice in contrast to the intestine whose dysfunction provokes a chronic K⁺ wasting in the feces. (C and D) Short circuit currents in colonic mucosa of kcne1^−/− and wild-type mice. A typical recording is shown in C. Arrows indicate the application of 10 μM amiloride. The averaged amiloride-sensitive calculated short circuit currents (ΔI_sc) are shown in D.

Figure 5

Tissue localization of KCNE1 and KCNQ1 expression. (A) RT-PCR analysis of KCNE1 and KCNQ1 mRNA in the kidneys, colon, and adrenal glands of wild-type mice. (B) In situ hybridization analysis of KCNE1 mRNA in the zona glomerulosa of toluidine blue counterstained adrenal sections of wild-type mice. No signal is detected in sections from kcne1^−/− mice (data not shown).