Modest dietary K⁺ restriction provokes insulin resistance of cellular K⁺ uptake and phosphorylation of renal outer medulla K⁺ channel without fall in plasma K⁺ concentration

Abstract

Extracellular K(+) concentration ([K(+)]) is closely regulated by the concerted regulatory responses of kidney and muscle. In this study, we aimed to define the responses activated when dietary K(+) was moderately reduced from a control diet (1.0% K(+)) to a 0.33% K(+) diet for 15 days. Although body weight and baseline plasma [K(+)] (4.0 mM) were not reduced in the 0.33% K(+) group, regulatory responses to conserve plasma [K(+)] were evident in both muscle and kidney. Insulin-stimulated clearance of K(+) from the plasma was estimated in vivo in conscious rats with the use of tail venous and arterial cannulas. During infusion of insulin.(50 mU.kg(-1).min(-1)), plasma [K(+)] level fell to 3.2 +/- 0.1 mM in the 1.0% K(+) diet group and to only 3.47 +/- 0.07 mM in the 0.33% K(+) diet group (P < 0.01) with no reduction in urinary K(+) excretion, which is evidence of insulin resistance to cellular K(+) uptake. Insulin-stimulated cellular K(+) uptake was quantitated by measuring the K(+) infusion rate necessary to clamp plasma K(+) at baseline (in micromol.kg(-1).min(-1)) during 5 mU of insulin.kg(-1).min(-1) infusion: 9.7 +/- 1.5 in 1% K(+) diet was blunted to 5.2 +/- 1.7 in the 0.33% K(+) diet group (P < 0.001). Muscle [K(+)] and Na(+)-K(+)-ATPase activity and abundance were unchanged during the 0.33% K(+) diet. Renal excretion, which was measured overnight in metabolic cages, was reduced by 80%, from 117.6 +/- 10.5 micromol/h/animal (1% K(+) diet) to 24.2 +/- 1.7 micromol/h/animal (0.33% K(+) diet) (P < 0.001). There was no significant change in total abundance of key renal K(+) transporters, but 50% increases in both renal PTK cSrc abundance and ROMK phosphorylation in the 0.33% K(+) vs. 1% K(+) diet group, previously established to be associated with internalization of ROMK. These results indicate that plasma [K(+)] can be maintained during modest K(+) restriction due to a decrease in insulin-stimulated cellular K(+) uptake as well as renal K(+) conservation mediated by inactivation of ROMK, both without a detectable change in plasma [K(+)]. The error signals inciting and maintaining these responses remain to be identified.

Chronic potassium depletion increases adrenal progesterone production that is necessary for efficient renal retention of potassium

“…Thus, this effect cannot be part of the hypokalemia-independent process described by McDonough's group. 20,21 Two potential steroid response elements in the promoter of the cHKa gene have been identified 22 and correlated with the aldosterone-induced stimulation of cHKA in the colon under a low-Na þ diet. 23 Based on our present observations, we speculate that the presence of these steroid response elements may partly explain how cHKA expression can be stimulated by progesterone and its nuclear receptor in low-K þ conditions.…”

AMPK activation with AICAR provokes an acute fall in plasma [K+]

“…To test the hypothesis that AMPK activation could play a role in clearing K ϩ from the ECF, conscious rats were infused with AICAR (bolus of 38.4 mg/kg then continuously at 4 mg⅐kg Ϫ1 ⅐min Ϫ1 in saline) through a tail vein while real time plasma [K ϩ ] and [glucose] were measured every 10 min and [glucose] clamped at baseline as described (8,10). Controls, assayed in parallel on the same day and time, were infused with a matched volume of saline (n ϭ 6 pairs).…”

“…This hypothesis was tested in vivo in conscious rats, using real time plasma [K ϩ ] and [glucose] measurements and clamps as implemented in our previous studies (8,10), and in mice deficient in muscle AMPK activity (34). AMPK was activated by infusion of 5-aminoimidazole-4-carboxamide 1-␤-D-ribofuranoside (AICAR), an adenosine analog that is converted to AICAR monophosphate (ZMP) after cellular uptake.…”

Inhibition of ROMK channels by low extracellular K+ and oxidative stress

“…ROMK activity was reported to be reduced in some (1,13) but not other (25,39) studies. The downregulation is thought to be mediated, at least in part, by activation of the tyrosine kinase c-src (4,22,39). ROMK protein expression is also reduced by low K intake (11,36).…”