Effects of extreme potassium stress on blood pressure and renal tubular sodium transport

Abstract

We characterized mouse blood pressure and ion transport in the setting of commonly used rodent diets that drive K+ intake to the extremes of deficiency and excess. Male 129S2/Sv mice were fed either K+-deficient, control, high-K+ basic, or high-KCl diets for 10 days. Mice maintained on a K+-deficient diet exhibited no change in blood pressure, whereas K+-loaded mice developed an ~10-mmHg blood pressure increase. Following challenge with NaCl, K+-deficient mice developed a salt-sensitive 8 mmHg increase in blood pressure, whereas blood pressure was unchanged in mice fed high-K+ diets. Notably, 10 days of K+ depletion induced diabetes insipidus and upregulation of phosphorylated NaCl cotransporter, proximal Na+ transporters, and pendrin, likely contributing to the K+-deficient NaCl sensitivity. While the anionic content with high-K+ diets had distinct effects on transporter expression along the nephron, both K+ basic and KCl diets had a similar increase in blood pressure. The blood pressure elevation on high-K+ diets correlated with increased Na+-K+-2Cl− cotransporter and γ-epithelial Na+ channel expression and increased urinary response to furosemide and amiloride. We conclude that the dietary K+ maneuvers used here did not recapitulate the inverse effects of K+ on blood pressure observed in human epidemiological studies. This may be due to the extreme degree of K+ stress, the low-Na+-to-K+ ratio, the duration of treatment, and the development of other coinciding events, such as diabetes insipidus. These factors must be taken into consideration when studying the physiological effects of dietary K+ loading and depletion.

KS-WNK1 amplifies kidney tubule responsiveness to potassium via WNK body condensates

“…Aside from effects on NCC, the relative hypokalemia observed in K+ restricted KS-WNK1-KO females could additionally be due to effects on other factors that mediate potassium secretion in the distal nephron, such as aldosterone, the epithelial sodium channel (ENaC), and the renal outer medullary potassium channel, ROMK. As reported previously, potassium restriction was associated with increased expression of the uncleaved form of the ENaC gamma subunit ( Fig S3A,B) and reduced ROMK protein abundance ( Fig S3A,C) [17]. Potassium-restricted female KS-WNK1-KO mice exhibited lower gamma ENaC abundance relative to WT mice ( Fig S3B).…”

“…Immunoblotting. For protein quantification, kidney cortexes were flash frozen and processed as previously described [17]. Ice-cold RIPA buffer (Thermo Scientific) was used for protein extraction with freshly added protease and phosphatase inhibitor cocktail.…”

“…To more fully assess the role of KS-WNK1 in NCC phosphorylation across the physiologic range of plasma [K+], KS-WNK1-KO mice and wild-type littermates (WT) were administered diets with low, standard, or high potassium content for 10 days. Since mice with normal GFR efficiently excrete a potassium load [17,18], we supplemented the high K+ diet-fed mice with amiloride (2mg/kg/day) to induce frank hyperkalemia. We then assessed NCC abundance and phosphorylation status via immunoblotting ( Figs 1A,B).…”

Water and Electrolyte Homeostasis in a Mouse Model with Reduced ENaC Gamma Subunit Expression

“…In the aldosterone-sensitive distal nephron, ENaC-mediated Na + reabsorption is tightly linked to K + excretion. Pharmacologic or genetic impairment of ENaC activity reduce K + secretion and promote hyperkalemia (4,6). It is therefore surprising that  mt/mt mice exhibit blood K + levels similar to controls.…”

Kidney Is Essential for Blood Pressure Modulation by Dietary Potassium

“…Many suggest that higher potassium intake attenuates salt-sensitivity [ 36 , 37 ], an effect corroborated in animal models [ 38 ]. The beneficial effects potassium may not, however, be uniform; recent animal studies and a meta-analysis of randomized-controlled trials suggest that excessive potassium intake may increase blood pressure [ 39 , 40 •]. The most impressive pressure-lowering effects of potassium are consistently observed when dietary salt consumption is also high.…”