Rapid development of vasopressin resistance in dietary K+ deficiency.

The association between diabetes insipidus (DI) and chronic dietary K+ deprivation is well known, but it remains uncertain how the disorder develops and whether it is influenced by the sexual dimorphism in K+ handling. Here, we determined the plasma K+ (PK) threshold for DI in male and female mice and ascertained if DI is initiated by polydipsia or by a central or nephrogenic defect. C57BL6J mice were randomized to a control diet or to graded reductions in dietary K+ for 8 days, and kidney function and transporters involved in water balance were characterized. We found that male and female mice develop polyuria and secondary polydipsia. Altered water balance coincided with a decrease in aquaporin-2 (AQP2) phosphorylation and apical localization despite increased levels of the vasopressin surrogate marker copeptin. No change in the protein abundance of urea transporter-A1 was observed. The Na+-K+-2Cl- cotransporter decreased only in males. Desmopressin treatment failed to reverse water diuresis in K+-restricted mice. These findings indicate that even a small fall in PK is associated with nephrogenic DI (NDI), coincident with the development of altered AQP2 regulation, implicating low PK as a causal trigger of NDI. We found that PK decreased more in females, and, consequently, females were more prone to develop NDI. Together, these data indicate that AQP2 regulation is disrupted by a small decrease in PK and that the response is influenced by sexual dimorphism in K+ handling. These findings provide new insights into the mechanisms linking water and K+ balances and support defining the disorder as "potassium-dependent NDI."NEW & NOTEWORTHY This study shows that aquaporin-2 regulation is disrupted by a small fall in plasma potassium levels and the response is influenced by sexual dimorphism in renal potassium handling. The findings provided new insights into the mechanisms by which water balance is altered in dietary potassium deficiency and support defining the disorder as "potassium-dependent nephrogenic diabetes insipidus."

Potassium Intake and Blood Pressure: A Dose-Response Meta-Analysis of Randomized Controlled Trials.

Background Epidemiologic studies, including trials, suggest an association between potassium intake and blood pressure (BP). However, the strength and shape of this relationship is uncertain. Methods and Results We performed a meta-analysis to explore the dose-response relationship between potassium supplementation and BP in randomized-controlled trials with a duration ≥4 weeks using the recently developed 1-stage cubic spline regression model. This model allows use of trials with at least 2 exposure categories. We identified 32 eligible trials. Most were conducted in adults with hypertension using a crossover design and potassium supplementation doses that ranged from 30 to 140 mmol/d. We observed a U-shaped relationship between 24-hour active and control arm differences in potassium excretion and BP levels, with weakening of the BP reduction effect above differences of 30 mmol/d and a BP increase above differences ≈80 mmol/d. Achieved potassium excretion analysis also identified a U-shaped relationship. The BP-lowering effects of potassium supplementation were stronger in participants with hypertension and at higher levels of sodium intake. The BP increase with high potassium excretion was noted in participants with antihypertensive drug-treated hypertension but not in their untreated counterparts. Conclusions We identified a nonlinear relationship between potassium intake and both systolic and diastolic BP, although estimates for BP effects of high potassium intakes should be interpreted with caution because of limited availability of trials. Our findings indicate an adequate intake of potassium is desirable to achieve a lower BP level but suggest excessive potassium supplementation should be avoided, particularly in specific subgroups.

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

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.

Renal potassium physiology: integration of the renal response to dietary potassium depletion.

We summarize the current understanding of the physiology of the renal handling of potassium (K+), and present an integrative view of the renal response to K+ depletion caused by dietary K+ restriction. This renal response involves contributions from different nephron segments, and aims to diminish the rate of excretion of K+ as a result of: decreasing the rate of electrogenic (and increasing the rate of electroneutral) reabsorption of sodium in the aldosterone-sensitive distal nephron (ASDN), decreasing the abundance of renal outer medullary K+ channels in the luminal membrane of principal cells in the ASDN, decreasing the flow rate in the ASDN, and increasing the reabsorption of K+ in the cortical and medullary collecting ducts. The implications of this physiology for the association between K+ depletion and hypertension, and K+ depletion and formation of calcium kidney stones are discussed.

The Effect of the Sodium to Potassium Ratio on Hypertension Prevalence: A Propensity Score Matching Approach.

This study investigated the effect of the sodium to potassium ratio on hypertension prevalence and blood pressure. The study population was constructed by pooling the Korean National Health and Nutrition Examination Surveys between 2010 and 2014. The study population was divided into quartiles based on the sodium to potassium ratio, and the effect was inferred by the difference in hypertension prevalence across quartiles by six pairwise comparisons using a propensity score matching technique. The quartiles with the higher sodium to potassium ratio had higher hypertension prevalence rates based on the following pairwise comparisons: the first vs. third quartile, the first vs. fourth quartile, the second vs. third quartile, and the second vs. fourth quartile. The prevalence differences were 2.74% point (p < 0.05), 3.44% point (p < 0.01), 2.47% point (p < 0.05), and 2.95% point (p < 0.01), respectively. In addition, statistically significant higher systolic (p < 0.05) and diastolic blood pressure (p < 0.01) was observed in the second quartiles compared to the first quartiles. Because a strong association was also detected between the sodium to potassium ratio and blood pressure even at a low level of sodium to potassium ratio, a lower sodium to potassium ratio diet than a usual diet is recommended to control high blood pressure in Korea.

Potassium Intake, Bioavailability, Hypertension, and Glucose Control.

Potassium is an essential nutrient. It is the most abundant cation in intracellular fluid where it plays a key role in maintaining cell function. The gradient of potassium across the cell membrane determines cellular membrane potential, which is maintained in large part by the ubiquitous ion channel the sodium-potassium (Na+-K+) ATPase pump. Approximately 90% of potassium consumed (60-100 mEq) is lost in the urine, with the other 10% excreted in the stool, and a very small amount lost in sweat. Little is known about the bioavailability of potassium, especially from dietary sources. Less is understood on how bioavailability may affect health outcomes. Hypertension (HTN) is the leading cause of cardiovascular disease (CVD) and a major financial burden ($50.6 billion) to the US public health system, and has a significant impact on all-cause morbidity and mortality worldwide. The relationship between increased potassium supplementation and a decrease in HTN is relatively well understood, but the effect of increased potassium intake from dietary sources on blood pressure overall is less clear. In addition, treatment options for hypertensive individuals (e.g., thiazide diuretics) may further compound chronic disease risk via impairments in potassium utilization and glucose control. Understanding potassium bioavailability from various sources may help to reveal how specific compounds and tissues influence potassium movement, and further the understanding of its role in health.

Why Your Mother Was Right: How Potassium Intake Reduces Blood Pressure.

Low potassium intake, common in western diets, increases blood pressure and enhances salt-sensitivity. Most humans in "Westernized" countries also consume excess salt. In studies using mice, we found that a high-salt, low-potassium diet activates the thiazide-sensitive Na-Cl cotransporter in the kidney. This effect led to sodium retention and increased blood pressure, and was dependent on plasma potassium. We postulated that this effect was mediated by changes in intracellular chloride caused by changes in membrane voltage. We developed a model in cultured cells permitting us to confirm this hypothesis. We then confirmed, using urinary exosomes, that dietary changes in normal humans, affect the thiazide-sensitive Na-Cl cotransporter in the same way. These data show that dietary potassium deficiency increases blood pressure largely by stimulating salt reabsorption along the distal nephron. They suggest that global efforts should focus on increasing potassium intake, which will attenuate the effects of high-salt diets.

The impact of sodium and potassium on hypertension risk.

The pathogenic role of sodium surfeit in primary hypertension is widely recognized but that of potassium deficiency usually has been ignored or at best assigned subsidiary status. Weighing the available evidence, we recently proposed that the chief environmental factor in the pathogenesis of primary hypertension and the associated cardiovascular risk is the interaction of the sodium surfeit and potassium deficiency in the body. Here, we present the major evidence highlighting the relationship between high-sodium intake and hypertension. We then examine the blood pressure-lowering effects of potassium in conjunction with the pernicious impact of potassium deficiency on hypertension and cardiovascular risk. We conclude with summarizing recent human trials that have probed the joint effects of sodium and potassium intake on hypertension and its cardiovascular sequelae. The latter studies lend considerable fresh support to the thesis that the interaction of the sodium surfeit and potassium deficiency in the body, rather than either disturbance by itself, is the critical environmental factor in the pathogenesis of hypertension.

Potassium-rich diet and risk of stroke: updated meta-analysis.

Recently a few prospective population studies provided additional and heterogeneous information concerning the reported statistical associations between potassium (K) intake and stroke risk. Therefore, we updated our previous meta-analysis of K intake and risk of cerebrovascular events. Three studies were added to the previous analysis, and the results of the comparison between the event rate in the two extreme categories of K intake were used. Pooled analysis of 14 cohorts (overall 333,250 participants and 10,659 events) showed an inverse and significant association between K intake and risk of stroke (Relative Risk: 0.80; 95% CI: 0.72-0.90). Our results indicated a favorable effect of higher K intake on risk of stroke. These results confirm the appropriateness of worldwide recommendations for a population increased consumption of potassium-rich foods to prevent cardiovascular disease.

Association of dietary sodium and potassium intakes with albuminuria in normal-weight, overweight, and obese participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study.

BACKGROUND: Among obese adults, sodium intake has been associated with cardiovascular disease. Few data are available on sodium intake and albuminuria, a marker of kidney damage and risk factor for cardiovascular disease. OBJECTIVE: We examined the relation between dietary sodium and potassium intakes and the ratio of sodium to potassium (Na/K) with albuminuria by BMI in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study (n = 30,239 adults aged ≥45 y). DESIGN: A modified Block 98 food-frequency questionnaire was used for dietary assessment in 21,636 participants, and nutritional variables were categorized by sex-specific quintiles. Normal weight, overweight, and obese were defined as BMI (in kg/m(2)) categories of 18.5-24.9, 25-29.9, and ≥30, respectively. Albuminuria was defined as a ratio (mg/g) of urinary albumin to creatinine of ≥30. RESULTS: The prevalences of albuminuria were 11.5%, 11.6%, and 16.0% in normal-weight, overweight, and obese participants, respectively. The multivariable-adjusted ORs for albuminuria in a comparison of the highest with the lowest quintile of Na/K intake (≥1.12 to <0.70 for men and ≥1.07 to <0.62 for women) were 0.89 (95% CI: 0.65, 1.22), 1.08 (95% CI: 0.85, 1.36), and 1.28 (95% CI: 1.02, 1.61) in normal-weight, overweight, and obese participants, respectively. The highest quintile of dietary sodium was associated with an increased OR for albuminuria in obese participants (OR: 1.44; 95% CI: 1.00, 2.07) but not in normal-weight or overweight participants. Dietary potassium was not associated with albuminuria. CONCLUSION: In obese adults, higher dietary Na/K and sodium intakes were associated with albuminuria.

Treatment of hypokalemic periodic paralysis with topiramate.

Hypokalemic periodic paralysis (hypoPP), the most common form of periodic paralysis, is a disorder characterized by attacks of transient muscle weakness associated with a drop in serum potassium level.The mainstay of treatment is potassium supplementation and drugs that inhibit the enzyme carbonic anhydrase. In this report we describe 11-year-old twins with hypoPP who were treated with topiramate, an anti-epileptic drug known to have carbonic anhydrase inhibitory properties. The patients experienced a decrease in the severity of their attacks upon initiation of treatment. Topiramate may warrant further investigation as a treatment option in hypoPP.

Elementary, my dear Dr. Allen: the case of barium toxicity and Pa Ping.

OBJECTIVE: We aimed to review the English and Chinese literature on Pa Ping and to confirm by personal interview the story of how its pathogenesis was uncovered. BACKGROUND: In 1930, Dr. Alexander Stewart Allen noticed a pattern of illness arising in the region of Kiating, China. Area residents began presenting to local hospitals with nausea, vomiting, and diarrhea, and what emerged was a clinical picture of a gradual ascending paralysis that could result in death, termed Pa Ping. All 3 patients observed by Dr. Allen were male, had no family history of the disease, and had recently eaten before the onset of paralysis. Pa Ping developed in Dr. Allen himself, but he survived. METHODS: Medical literature was reviewed for primary sources. Interviews of living descendants and friends of the doctors in China and North America were conducted and information was corroborated by written records. RESULTS: Dr. Huang, with the National Central University College of Medicine, noticed a striking similarity between Pa Ping and familial periodic paralysis in 12 patients and reported 2 patients with Pa Ping treated with potassium citrate who experienced a reversal of the paralysis. Dr. K.T. Du analyzed meals of patients with Pa Ping seen by Dr. Zhe Tung and found barium in concentrations as high as 25.7%. This finding was confirmed by administering barium chloride to animals, which recapitulated the human syndrome. CONCLUSIONS: Although Dr. Huang had correctly noticed an underlying potassium depletion in patients with Pa Ping, the observations of Dr. Zhe Tung and Dr. K.T. Du ultimately established barium-induced hypokalemia as the underlying cause.

Andersen cardiodysrhythmic periodic paralysis with KCNJ2 mutations: a novel mutation in the pore selectivity filter residue.

Andersen cardiodysrhythmic periodic paralysis or Andersen-Tawil syndrome includes the distinct clinical features of periodic paralysis, cardiac arrhythmia, and facial and skeletal dysmorphisms and exhibits autosomal dominant inheritance. Mutations in the KCNJ2 gene, which encodes the human inward rectifier potassium channel Kir2.1, have been identified in the majority of cases. Despite well-established clinical and molecular characteristics, treatment is still case oriented, and timely diagnosis could be delayed because of the low incidence and phenotypic heterogeneity of this disease. This article describes the clinical and molecular features of 3 cases of Andersen-Tawil syndrome in 2 families. One of the mutations (G144D) was located in the pore selectivity filter residue (which is mutated recurrently) and was considered novel. Intermittent muscle weakness in childhood warrants careful evaluation of cardiac dysrhythmia and skeletal anomalies.

Diuretic-induced potassium depletion and glucose intolerance are not related to hyperactivity of the renin-angiotensin-aldosterone system in hypertensive patients with the metabolic syndrome.

The metabolic syndrome (MS) has been associated with hyperactivity of the renin-angiotensin-aldosterone system (RAAS). To assess the hypothesis that diuretic therapy in MS patients through further stimulation of RAAS would elicit greater potassium (K) depletion, two groups of hypertensive patients with (MS group [MSG]; n=20) and without (control group [CG]; n=19) MS were studied. Plasma renin activity (PRA), aldosterone (PA), and K levels were determined and an oral glucose tolerance test with plasma insulin determinations for calculation of homeostasis model assessment of insulin resistance (HOMA-IR), sensitivity (ISI), and secretion (HOMA-beta) was performed, both before and 12 weeks after hydrochlorothiazide (HCT; 25 mg/d) therapy. At baseline, higher HOMA IR and HOMA-beta and lower ISI and plasma K were found in the MSG than in the CG, with no differences in PA and PRA between groups. With therapy, PRA increased similarly in both groups while PA increased only in the MSG. However, greater reduction in plasma K occurred in the CG, and the 2 groups reached similar final K values. Impairment in glucose tolerance occurred in both groups, with no change in HOMA-beta in the CG and reduction in the MSG, suggesting that diuretic therapy increases insulin resistance and impairs insulin secretion independent of abdominal obesity. These alterations could not be attributed to hyperactivity of RAAS.

NOX2 mediates apoptotic death induced by staurosporine but not by potassium deprivation in cerebellar granule neurons.

Neuronal apoptotic death involves the participation of reactive oxygen species (ROS), but their sources have not been completely elucidated. Previous studies have demonstrated that the ROS-producing enzyme NADPH oxidase is present in neuronal cells and that this enzyme could participate in the apoptotic neuronal death. Cerebellar granule neurons (CGN) undergo apoptosis when cells are transferred from a medium with 25 mM KCl (K25) to a 5 mM KCl (K5) medium or when they are treated with staurosporine (ST). Under these conditions, apoptotic death of CGN is dependent on ROS production. In this study, we evaluated the role of NOX2, an NADPH oxidase homolog, in the apoptotic death of CGN induced by two different conditions. In CGN from NOX2-deficient (ko) mice, a significantly lower rate of apoptotic death occurs compared with wild-type (wt) CGN. Also, caspase-3 activation, NADPH oxidase activity, and superoxide anion production induced by ST were markedly lower in ko neurons than in wt CGN. In contrast to the case with ST, when CGN were treated with K5, no differences were observed between ko and wt cells in any of the parameters measured. However, all NADPH oxidase inhibitors tested noticeably reduced cell death and apoptotic parameters induced by K5 in both wt and ko CGN. These results suggest that NOX2 could be necessary for apoptotic death induced by ST, but not by K5, which could require other member of the NOX family in the apoptotic process.

Regulation of phosphate transport in proximal tubules.

Homeostasis of inorganic phosphate (P(i)) is primarily an affair of the kidneys. Reabsorption of the bulk of filtered P(i) occurs along the renal proximal tubule and is initiated by apically localized Na(+)-dependent P(i) cotransporters. Tubular P(i) reabsorption and therefore renal excretion of P(i) is controlled by a number of hormones, including phosphatonins, and metabolic factors. In most cases, regulation of P(i) reabsorption is achieved by changing the apical abundance of Na(+)/Pi cotransporters. The regulatory mechanisms involve various signaling pathways and a number of proteins that interact with Na(+)/P(i) cotransporters.

The Kv2.1 channels mediate neuronal apoptosis induced by excitotoxicity.

Chronic loss of intracellular K(+) can induce neuronal apoptosis in pathological conditions. However, the mechanism by which the K(+) channels are regulated in this process remains largely unknown. Here, we report that the increased membrane expression of Kv2.1 proteins in cortical neurons deprived of serum, a condition known to induce K(+) loss, promotes neuronal apoptosis. The increase in I(K) current density and apoptosis in the neurons deprived of serum were inhibited by a dominant negative form of Kv2.1 and MK801, an antagonist to NMDA receptors. The membrane level of Kv2.1 and its interaction with SNAP25 were increased, whereas the Kv2.1 phosphorylation was inhibited in the neurons deprived of serum. Botulinum neurotoxin, an agent known to prevent formation of soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex, suppressed the increase in I(K) current density. Together, these results suggest that NMDA receptor-dependent Kv2.1 membrane translocation is regulated by a soluble N-ethylmaleimide-sensitive factor attachment protein receptor-dependent vesicular trafficking mechanism and is responsible for neuronal cell death induced by chronic loss of K(+).

Licking for taste solutions by potassium-deprived rats: specificity and mechanisms.

There has been little work on the specificity and mechanisms underlying the appetite of potassium (K(+)) deprived rats, and there are conflicting results. To investigate the contribution of oral factors to changes in intake induced by K(+) deficiency, we conducted two experiments using 20-s "brief access" tests. In Experiment 1, K(+)-deprived rats licked less for water than did replete rats. After adjusting for this difference, K(+)-deprived rats exhibited increased licking for 100 mM CaCl(2), 100 mM MgCl(2), and 100 mM FeCl(2) compared with K(+)-replete rats. In Experiment 2, which used larger rats, the K(+)-deprived and replete groups licked equally for water, 500 mM Na.Gluconate, 350 mM KCl, 500 mM KHCO(3), and 1 mM quinine.HCl, but the K(+)-deprived rats licked more for 500 mM KCl, 500 mM CsCl, and 500 mM NaCl than did the replete rats. Licking was unaffected by addition to NaCl of 200 muM amiloride, an epithelial Na(+) channel (ENaC) blocker, or 100 muM ruthenium red, a vanilloid receptor 1 (VR-1) antagonist, or by addition to KCl of 50 muM 4-aminopyridine, a K(+) channel blocker. These findings suggest that K(+)-deprivation produces a non-specific appetite that is guided by oral factors. We found no evidence that this response was mediated by ENaC, VR-1, or K(+) channels in taste receptor cells.

Activating transcription factor 3 up-regulated by c-Jun NH(2)-terminal kinase/c-Jun contributes to apoptosis induced by potassium deprivation in cerebellar granule neurons.

Cerebellar granule neurons (CGNs) depend on potassium depolarization for survival and undergo apoptosis when deprived of depolarizing concentration of potassium. Activating transcription factor 3 (ATF3), a stress-inducible protein, belongs to the ATF/CREB family of transcription factors family and is involved in cell growth and apoptosis. However, the role of ATF3 in neuronal apoptosis remains unknown. Here, we showed that ATF3 was up-regulated under potassium deprivation in CGNs, and this induction was preceded by a rapid and sustained activation of c-Jun NH(2)-terminal kinase/c-Jun signaling pathway, which plays a fundamental role in neuronal apoptosis. Furthermore, ATF3 up-regulation was abolished by inhibition of JNK or knockdown of c-Jun. Finally, knockdown of ATF3 by RNA interference protected CGNs from potassium deprivation-induced apoptosis. Taken together, our results indicate that ATF3 is a downstream target of JNK/c-Jun pathway and contributes to apoptosis induced by potassium deprivation in rat CGNs.

Reduced expression of Kir6.2/SUR2A subunits explains KATP deficiency in K+-depleted rats.

We investigated on the mechanism responsible for the reduced ATP-sensitive K(+)(K(ATP)) channel activity recorded from skeletal muscle of K(+)-depleted rats. Patch-clamp and gene expression measurements of K(ATP) channel subunits were performed. A down-regulation of the K(ATP) channel subunits Kir6.2(-70%) and SUR2A(-46%) in skeletal muscles of K(+)-depleted rats but no changes in the expression of Kir6.1, SUR1 and SUR2B subunits were observed. A reduced K(ATP) channel currents of -69.5% in K(+)-depleted rats was observed. The Kir6.2/SUR2A-B agonist cromakalim showed similar potency in activating the K(ATP) channels of normokalaemic and K(+)-depleted rats but reduced efficacy in K(+)-depleted rats. The Kir6.2/SUR1-2B agonist diazoxide activated K(ATP) channels in normokalaemic and K(+)-depleted rats with equal potency and efficacy. The down-regulation of the Kir6.2 explains the reduced K(ATP) channel activity in K(+)-depleted rats. The lower expression of SUR2A explains the reduced efficacy of cromakalim; preserved SUR1 expression accounts for the efficacy of diazoxide. Kir6.2/SUR2A deficiency is associated with impaired muscle function in K(+)-depleted rats and in hypoPP.