Search

Inadequate dietary potassium (K + ) consumption is a significant contributor to poor cardiovascular outcomes. A diet with reduced K + content has been shown to cause salt-sensitive increases in blood pressure. More recently, we have also shown that reductions in blood K + can cause direct kidney injury, independent of dietary sodium (Na + ) content. Here, we investigated the role of the kinase Ste20p-related proline-alanine-rich kinase (SPAK) in this kidney injury response. We observed that global SPAK deletion protected the kidney from the damaging effects of a diet high in Na + and low in K + . We hypothesized that kidney macrophages were contributing to the injury response and that macrophage-expressed SPAK is essential in this process. We observed SPAK protein expression in isolated macrophages in vitro. Culture in K + -deficient medium increased SPAK phosphorylation and caused SPAK to localize to cytosolic puncta, reminiscent of with-no-lysine kinase (WNK) bodies identified along the distal nephron epithelium. WNK1 also adopted a punctate staining pattern under low K + conditions, and SPAK phosphorylation was prevented by treatment with the WNK inhibitor WNK463. Macrophage-specific SPAK deletion in vivo protected against the low K + -mediated renal inflammatory and fibrotic responses. Our results highlight an important role for macrophages and macrophage-expressed SPAK in the propagation of kidney damage that occurs in response to reduced dietary K + consumption. NEW & NOTEWORTHY Global Ste20p-related proline alanine-rich kinase (SPAK) deletion protects against harmful kidney effects of dietary K + deficiency. Exposure to low K + conditions increases SPAK phosphorylation and induces SPAK to adopt a punctate staining pattern. Macrophage-specific deletion of SPAK confers protection to low K + -induced kidney injury in vivo. Macrophage-expressed SPAK plays a key role in the development of kidney injury in response to a low K + diet.

Maintaining extracellular potassium (K + ) within narrow limits, critical for membrane potential and excitability, is accomplished through the internal redistribution of K + between extracellular fluid (ECF) and intracellular fluid (ICF) in concert with the regulation of renal K + output to balance K + intake. Here we present evidence from high-precision analyses of stable K + isotopes in rats maintained on a control diet that the tissues and organs involved in the internal redistribution of K + differ in their speed of K + exchange with ECF and can be grouped into those that exchange K + with ECF either rapidly or more slowly ("fast" and "slow" pools). After 10 days of K + restriction, a compartmental analysis indicates that the sizes of the ICF K + pools decreased but that this decrease in ICF K + pools was not homogeneous, rather occurring only in the slow pool (15% decrease, p < 0.01), representing skeletal muscles, not in the fast pool. Furthermore, we find that the dietary K + restriction is associated with a decline in the rate constants for K + effluxes from both the "fast" and "slow" ICF pools ( p < 0.05 for both). These results suggest that changes in unidentified transport pathways responsible for K + efflux from ICF to ECF play an important role in buffering the internal redistribution of K + between ICF and ECF during K + restriction. Thus, the present study introduces novel stable isotope approaches to separately characterize heterogenous ICF K + pools in vivo and assess K + uptake by individual tissues, methods that provide key new tools to elucidate K + homeostatic mechanisms in vivo.

Dietary potassium deficiency causes stimulation of sodium reabsorption leading to an increased risk in blood pressure elevation. The distal convoluted tubule (DCT) is the main rheostat linking plasma K + levels to the activity of the Na-Cl cotransporter (NCC). This occurs through basolateral membrane potential sensing by inwardly rectifying K + channels (Kir4.1/5.1); decrease in intracellular Cl - ; activation of WNK4 and interaction and phosphorylation of STE20/SPS1-related proline/alanine-rich kinase (SPAK); binding of calcium-binding protein 39 (cab39) adaptor protein to SPAK, leading to its trafficking to the apical membrane; and SPAK binding, phosphorylation, and activation of NCC. As kidney-specific with-no-lysine kinase 1 (WNK1) isoform (KS-WNK1) is another participant in this pathway, we examined its function in NCC regulation. We eliminated KS-WNK1 specifically in the DCT and demonstrated increased expression of WNK4 and long WNK1 (L-WNK1) and increased phosphorylation of NCC. As in other KS-WNK1 models, the mice were not hyperkalemic. Although wild-type mice under low-dietary K + conditions demonstrated increased NCC phosphorylation, the phosphorylation levels of the transporter, already high in KS-WNK1, did not change under the low-K + diet. Thus, in the absence of KS-WNK1, the transporter lost its sensitivity to low plasma K + . We also show that under low K + conditions, in the absence of KS-WNK1, there was no formation of WNK bodies. These bodies were observed in adjacent segments, not affected by the targeting of KS-WNK1. As our data are overall consistent with those of the global KS-WNK1 knockout, they indicate that the DCT is the predominant segment affecting the salt transport regulated by KS-WNK1. NEW & NOTEWORTHY In this paper, we show that KS-WNK1 is a critical component of the distal convoluted tubule (DCT) K + switch pathway. Its deletion results in an inability of the DCT to sense changes in plasma potassium. Absence of KS-WNK1 leads to abnormally high levels of WNK4 and L-WNK1 in the DCT, resulting in increased Na-Cl phosphorylation and function. Our data are consistent with KS-WNK1 targeting WNK4 and L-WNK1 to degradation.

The pore-forming α-subunit of the large-conductance K + (BK) channel is encoded by a single gene, KCNMA1. BK channel-mediated K + secretion in the kidney is crucial for overall renal K + homeostasis in both physiological and pathological conditions. BK channels achieve phenotypic diversity by various mechanisms, including substantial exon rearrangements at seven major alternative splicing sites. However, KCNMA1 alternative splicing in the kidney has not been characterized. The present study aims to identify the major splice variants of mouse Kcnma1 in whole kidney and distal nephron segments. We designed primers that specifically cross exons within each alternative splice site of mouse Kcnma1 and performed real-time quantitative RT-PCR (RT-qPCR) to quantify relative abundance of each splice variant. Our data suggest that Kcnma1 splice variants within mouse kidney are less diverse than in the brain. During postnatal kidney development, most Kcnma1 splice variants at site 5 and the COOH terminus increase in abundance over time. Within the kidney, the regulation of Kcnma1 alternative exon splicing within these two sites by dietary K + loading is both site and sex specific. In microdissected distal tubules, the Kcnma1 alternative splicing profile, as well as its regulation by dietary K + , are distinctly different than in the whole kidney, suggesting segment and/or cell type specificity in Kcnma1 splicing events. Overall, our data provide evidence that Kcnma1 alternative splicing is regulated during postnatal development and may serve as an important adaptive mechanism to dietary K + loading in mouse kidney. NEW & NOTEWORTHY We identified the major Kcnma1 splice variants that are specifically expressed in the whole mouse kidney or aldosterone-sensitive distal nephron segments. Our data suggest that Kcnma1 alternative splicing is developmentally regulated and subject to changes in dietary K + .

Diabetes is closely associated with K + disturbances during disease progression and treatment. However, it remains unclear whether K + imbalance occurs in diabetes with normal kidney function. In this study, we examined the effects of dietary K + intake on systemic K + balance and renal K + handling in streptozotocin (STZ)-induced diabetic mice. The control and STZ mice were fed low or high K + diet for 7 days to investigate the role of dietary K + intake in renal K + excretion and K + homeostasis and to explore the underlying mechanism by evaluating K + secretion-related transport proteins in distal nephrons. K + -deficient diet caused excessive urinary K + loss, decreased daily K + balance, and led to severe hypokalemia in STZ mice compared with control mice. In contrast, STZ mice showed an increased daily K + balance and elevated plasma K + level under K + -loading conditions. Dysregulation of the NaCl cotransporter (NCC), epithelial Na + channel (ENaC), and renal outer medullary K + channel (ROMK) was observed in diabetic mice fed either low or high K + diet. Moreover, amiloride treatment reduced urinary K + excretion and corrected hypokalemia in K + -restricted STZ mice. On the other hand, inhibition of SGLT2 by dapagliflozin promoted urinary K + excretion and normalized plasma K + levels in K + -supplemented STZ mice, at least partly by increasing ENaC activity. We conclude that STZ mice exhibited abnormal K + balance and impaired renal K + handling under either low or high K + diet, which could be primarily attributed to the dysfunction of ENaC-dependent renal K + excretion pathway, despite the possible role of NCC. NEW & NOTEWORTHY Neither low dietary K + intake nor high dietary K + intake effectively modulates renal K + excretion and K + homeostasis in STZ mice, which is closely related to the abnormality of ENaC expression and activity. SGLT2 inhibitor increases urinary K + excretion and reduces plasma K + level in STZ mice under high dietary K + intake, an effect that may be partly due to the upregulation of ENaC activity.

Klotho regulates many pathways in the aging process, but it remains unclear how it is physiologically regulated. Because Klotho is synthesized, cleaved, and released from the kidney; activates the chief urinary K + secretion channel (ROMK) and stimulates urinary K + secretion, we explored if Klotho protein is regulated by dietary K + and the potassium-regulatory hormone, Aldosterone. Klotho protein along the nephron was evaluated in humans and in wild-type (WT) mice; and in mice lacking components of Aldosterone signaling, including the Aldosterone-Synthase KO (AS-KO) and the Mineralocorticoid-Receptor KO (MR-KO) mice. We found the specific cells of the distal nephron in humans and mice that are chief sites of regulated K + secretion have the highest Klotho protein expression along the nephron. WT mice fed K + -rich diets increased Klotho expression in these cells. AS-KO mice exhibit normal Klotho under basal conditions but could not upregulate Klotho in response to high-K + intake in the K + -secreting cells. Similarly, MR-KO mice exhibit decreased Klotho protein expression. Together, i) Klotho is highly expressed in the key sites of regulated K + secretion in humans and mice, ii) In mice, K + -rich diets increase Klotho expression specifically in the potassium secretory cells of the distal nephron, iii) Aldosterone signaling is required for Klotho response to high K + intake., (© 2024. The Author(s).)

Osteoporosis is a significant public health concern, particularly in aging populations, leading to fractures, decreased mobility, and reduced quality of life. While calcium and vitamin D have long been recognized as essential for bone health, emerging research suggests that potassium may play a crucial role in maintaining bone density and preventing osteoporosis. This manuscript explores the relationship between potassium and osteoporosis, delving into the mechanisms, epidemiological evidence, and potential therapeutic implications of potassium in bone health. Furthermore, the manuscript discusses the sources of dietary potassium, its impact on bone metabolism, and the future directions in research and clinical practice regarding potassium's role in osteoporosis management., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Potassium (K + )-deficient diets, typical of modern processed foods, increase blood pressure (BP) and NaCl sensitivity. A K + -dependent signaling pathway in the kidney distal convoluted tubule, coined the K + switch, that couples extracellular K + sensing to activation of the thiazide-sensitive NaCl cotransporter (NCC) and NaCl retention has been implicated, but causality has not been established., Methods: To test the hypothesis that small, physiological changes in plasma K + (P K+ ) are translated to BP through the switch pathway, a genetic approach was used to activate the downstream switch kinase, SPAK (SPS1-related proline/alanine-rich kinase), within the distal convoluted tubule. The CA-SPAK (constitutively active SPS1-related proline/alanine-rich kinase mice) were compared with control mice over a 4-day P K+ titration (3.8-5.1 mmol) induced by changes in dietary K + . Arterial BP was monitored using radiotelemetry, and renal function measurements, NCC abundance, phosphorylation, and activity were made., Results: As P K+ decreased in control mice, BP progressively increased and became sensitive to dietary NaCl and hydrochlorothiazide, coincident with increased NCC phosphorylation and urinary sodium retention. By contrast, BP in CA-SPAK mice was elevated, resistant to the P K+ titration, and sensitive to hydrochlorothiazide and salt at all P K+ levels, concomitant with sustained and elevated urinary sodium retention and NCC phosphorylation and activity. Thus, genetically locking the switch on drives NaCl sensitivity and prevents the response of BP to potassium., Conclusions: Low K + , common in modern ultraprocessed diets, presses the K + -switch pathway to turn on NCC activity, increasing sodium retention, BP, and salt sensitivity., Competing Interests: Disclosures None.

Kidney-specific with-no-lysine kinase 1 (KS-WNK1) is an isoform of WNK1 kinase that is predominantly found in the distal convoluted tubule of the kidney. The precise physiological function of KS-WNK1 remains unclear. Some studies have suggested that it could play a role in regulating potassium renal excretion by modulating the activity of the Na + -Cl - cotransporter (NCC). However, changes in the potassium diet from normal to high failed to reveal a role for KS-WNK1, but under a normal-potassium diet, the expression of KS-WNK1 is negligible. It is only detectable when mice are exposed to a low-potassium diet. In this study, we investigated the role of KS-WNK1 in regulating potassium excretion under extreme changes in potassium intake. After following a zero-potassium diet (0KD) for 10 days, KS-WNK1 -/- mice had lower plasma levels of K + and Cl - while exhibiting higher urinary excretion of Na + , Cl - , and K + compared with KS-WNK1 +/+ mice. After 10 days of 0KD or normal-potassium diet (NKD), all mice were challenged with a high-potassium diet (HKD). Plasma K + levels markedly increased after the HKD challenge only in mice previously fed with 0KD, regardless of genotype. KSWNK1 +/+ mice adapt better to HKD challenge than KS-WNK1 -/- mice after a potassium-retaining state. The difference in the phosphorylated NCC-to-NCC ratio between KS-WNK1 +/+ and KS-WNK1 -/- mice after 0KD and HKD indicates a role for KS-WNK1 in both NCC phosphorylation and dephosphorylation. These observations show that KS-WNK1 helps the distal convoluted tubule to respond to extreme changes in potassium intake, such as those occurring in wildlife. NEW & NOTEWORTHY The findings of this study demonstrate that kidney-specific with-no-lysine kinase 1 plays a role in regulating urinary electrolyte excretion during extreme changes in potassium intake, such as those occurring in wildlife.  .

We have previously shown that an excess of deoxycorticosterone acetate and high sodium chloride intake (DOCA/salt) in one-renin gene mice induces a high urinary Na/K ratio, hypokalemia, and cardiac and renal hypertrophy in the absence of hypertension. Dietary potassium supplementation prevents DOCA/salt-induced pathological processes. In the present study, we further study whether DOCA/salt-treated mice progressively develop chronic inflammation and fibrosis in the kidney and whether dietary potassium supplementation can reduce the DOCA/salt-induced renal pathological process. Results showed that (1) long-term DOCA/salt-treated one-renin gene mice developed severe kidney injuries including tubular/vascular hypertrophy, mesangial/interstitial/perivascular fibrosis, inflammation (lymphocyte's immigration), proteinuria, and high serum creatinine in the absence of hypertension; (2) there were over-expressed mRNAs of plasminogen activator inhibitor-1 (PAI-1), fibronectin, collagen type I and III, interferon-inducible protein-10 (IP-10), monocyte chemotactic protein-1 (MCP1), transforming growth factor- β (TGF- β ), tumor necrosis factor-alpha (TNF- α ), osteopontin, Nuclear factor kappa B (NF-κB)/P65, and intercellular adhesion molecule (ICAM)-1; and (3) dietary potassium supplementation normalized urinary Na/K ratio, hypokalemia, proteinuria, and serum creatinine, reduced renal hypertrophy, inflammations, and fibrosis, and down-regulated mRNA expression of fibronectin, Col-I and III, TGF- β , TNF- α , osteopontin, and ICAM without changes in the blood pressure. The results provide new evidence that potassium and sodium may modulate proinflammatory and fibrotic genes, leading to chronic renal lesions independent of blood pressure.

Consumption of low dietary potassium, common with ultraprocessed foods, activates the thiazide-sensitive sodium chloride cotransporter (NCC) via the with no (K) lysine kinase/STE20/SPS1-related proline-alanine-rich protein kinase (WNK/SPAK) pathway to induce salt retention and elevate blood pressure (BP). However, it remains unclear how high-potassium "DASH-like" diets (dietary approaches to stop hypertension) inactivate the cotransporter and whether this decreases BP. A transcriptomics screen identified Ppp1Ca, encoding PP1A, as a potassium-upregulated gene, and its negative regulator Ppp1r1a, as a potassium-suppressed gene in the kidney. PP1A directly binds to and dephosphorylates NCC when extracellular potassium is elevated. Using mice genetically engineered to constitutively activate the NCC-regulatory kinase SPAK and thereby eliminate the effects of the WNK/SPAK kinase cascade, we confirmed that PP1A dephosphorylated NCC directly in a potassium-regulated manner. Prior adaptation to a high-potassium diet was required to maximally dephosphorylate NCC and lower BP in constitutively active SPAK mice, and this was associated with potassium-dependent suppression of Ppp1r1a and dephosphorylation of its cognate protein, inhibitory subunit 1 (I1). In conclusion, potassium-dependent activation of PP1A and inhibition of I1 drove NCC dephosphorylation, providing a mechanism to explain how high dietary K+ lowers BP. Shifting signaling of PP1A in favor of activation of WNK/SPAK may provide an improved therapeutic approach for treating salt-sensitive hypertension.

The urinary potassium (K + ) excretion machinery is upregulated with increasing dietary K + , but the role of accompanying dietary anions remains inadequately characterized. Poorly absorbable anions, including [Formula: see text], are thought to increase K + secretion through a transepithelial voltage effect. Here, we tested if they also influence the K + secretion machinery. Wild-type mice, aldosterone synthase (AS) knockout (KO) mice, or pendrin KO mice were randomized to control, high-KCl, or high-KHCO 3 diets. The K + secretory capacity was assessed in balance experiments. Protein abundance, modification, and localization of K + -secretory transporters were evaluated by Western blot analysis and confocal microscopy. Feeding the high-KHCO 3 diet increased urinary K + excretion and the transtubular K + gradient significantly more than the high-KCl diet, coincident with more pronounced upregulation of epithelial Na+ channels (ENaC) and renal outer medullary K + (ROMK) channels and apical localization in the distal nephron. Experiments in AS KO mice revealed that the enhanced effects of [Formula: see text] were aldosterone independent. The high-KHCO 3 diet also uniquely increased the large-conductance Ca 2+ -activated K + (BK) channel β 4 -subunit, stabilizing BKα on the apical membrane, the Cl - /[Formula: see text] exchanger, pendrin, and the apical KCl cotransporter (KCC3a), all of which are expressed specifically in pendrin-positive intercalated cells. Experiments in pendrin KO mice revealed that pendrin was required to increase K + excretion with the high-KHCO 3 diet. In summary, [Formula: see text] stimulates K + excretion beyond a poorly absorbable anion effect, upregulating ENaC and ROMK in principal cells and BK, pendrin, and KCC3a in pendrin-positive intercalated cells. The adaptive mechanism prevents hyperkalemia and alkalosis with the consumption of alkaline ash-rich diets but may drive K + wasting and hypokalemia in alkalosis. NEW & NOTEWORTHY Dietary anions profoundly impact K + homeostasis. Here, we found that a K + -rich diet, containing [Formula: see text] as the counteranion, enhances the electrogenic K + excretory machinery, epithelial Na + channels, and renal outer medullary K + channels, much more than a high-KCl diet. It also uniquely induces KCC3a and pendrin, in B-intercalated cells, providing an electroneutral KHCO 3 secretion pathway. These findings reveal new K + balance mechanisms that drive adaption to alkaline and K + -rich foods, which should guide new treatment strategies for K + disorders.

Mechanosensitive TRPV4 channel plays a dominant role in maintaining [Ca 2+ ] i homeostasis and flow-sensitive [Ca 2+ ] i signaling in the renal tubule. Polycystic kidney disease (PKD) manifests as progressive cyst growth due to cAMP-dependent fluid secretion along with deficient mechanosensitivity and impaired TRPV4 activity. Here, we tested how regulation of renal TRPV4 function by dietary K + intake modulates the rate of cystogenesis and mechanosensitive [Ca 2+ ] i signaling in cystic cells of PCK453 rats, a homologous model of human autosomal recessive PKD (ARPKD). One month treatment with both high KCl (5% K + ) and KB/C (5% K + with bicarbonate/citrate) diets significantly increased TRPV4 levels when compared to control (0.9% K + ). High KCl diet caused an increased TRPV4-dependent Ca 2+ influx, and partial restoration of mechanosensitivity in freshly isolated monolayers of cystic cells. Unexpectedly, high KB/C diet induced an opposite effect by reducing TRPV4 activity and worsening [Ca 2+ ] i homeostasis. Importantly, high KCl diet decreased cAMP, whereas high KB/C diet further increased cAMP levels in cystic cells (assessed as AQP2 distribution). At the systemic level, high KCl diet fed PCK453 rats had significantly lower kidney-to-bodyweight ratio and reduced cystic area. These beneficial effects were negated by a concomitant administration of an orally active TRPV4 antagonist, GSK2193874, resulting in greater kidney weight, accelerated cystogenesis, and augmented renal injury. High KB/C diet also exacerbated renal manifestations of ARPKD, consistent with deficient TRPV4 activity in cystic cells. Overall, we demonstrate that TRPV4 channel activity negatively regulates cAMP levels in cystic cells thus attenuating (high activity) or accelerating (low activity) ARPKD progression., (© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

The Cl - /[Formula: see text] exchanger pendrin in the kidney maintains acid-base balance and intravascular volume. Pendrin is upregulated in models associated with high circulating aldosterone concentration, such as dietary NaCl restriction or an aldosterone infusion. However, it has not been established if pendrin is similarly regulated by aldosterone with a high-K + diet because the effects of accompanying anions have not been considered. Here, we explored how pendrin is modulated by different dietary potassium salts. Wild-type (WT) and aldosterone synthase (AS) knockout (KO) mice were randomized to control, high-KHCO 3 , or high-KCl diets. Dietary KCl and KHCO 3 loading increased aldosterone in WT mice to the same extent but had opposite effects on pendrin abundance. KHCO 3 loading increased pendrin protein and transcript abundance. Conversely, high-KCl diet feeding caused pendrin to decrease within 8 h of switching from the high-KHCO 3 diet, coincident with an increase in plasma Cl - and a decrease in [Formula: see text]. In contrast, switching the high-KCl diet to the high-KHCO 3 diet caused pendrin to increase in WT mice. Experiments in AS KO mice revealed that aldosterone is necessary to optimally upregulate pendrin protein in response to the high-KHCO 3 diet but not to increase pendrin mRNA. We conclude that pendrin is differentially regulated by different dietary potassium salts and that its regulation is prioritized by the dietary anion, providing a mechanism to prevent metabolic alkalosis with high-K + base diets and safeguard against hyperchloremic acidosis with consumption of high-KCl diets. NEW & NOTEWORTHY Regulation of the Cl - /[Formula: see text] exchanger pendrin has been suggested to explain the aldosterone paradox. A high-K + diet has been proposed to downregulate a pendrin-mediated K + -sparing NaCl reabsorption pathway to maximize urinary K + excretion. Here, we challenged the hypothesis, revealing that the accompanying anion, not K + , drives pendrin expression. Pendrin is downregulated with a high-KCl diet, preventing acidosis, and upregulated with an alkaline-rich high-K + diet, preventing metabolic alkalosis. Pendrin regulation is prioritized for acid-base balance.

The renal outer medullary K + channel (ROMK) is colocalized with the epithelial Na + channel (ENaC) in the late distal convoluted tubule (DCT2), connecting tubule (CNT), and cortical collecting duct (CCD). ENaC-mediated Na + absorption generates the electrical driving force for ROMK-mediated tubular K + secretion, which is critically important for maintaining renal K + homeostasis. ENaC activity is aldosterone dependent in the late CNT and early CCD (CNT/CCD) but aldosterone independent in the DCT2 and early CNT (DCT2/CNT). This suggests that under baseline conditions with low plasma aldosterone, ROMK-mediated K + secretion mainly occurs in the DCT2/CNT. Therefore, we hypothesized that baseline ROMK activity is higher in the DCT2/CNT than in the CNT/CCD. To test this hypothesis, patch-clamp experiments were performed in the DCT2/CNT and CNT/CCD microdissected from mice maintained on a standard diet. In single-channel recordings from outside-out patches, we detected typical ROMK channel activity in both the DCT2/CNT and CNT/CCD and confirmed that ROMK is the predominant K + channel in the apical membrane. Amiloride-sensitive and tertiapin-sensitive whole-cell currents were determined to assess ENaC and ROMK activity, respectively. As expected, baseline amiloride-sensitive current was high in the DCT2/CNT (∼370 pA) but low in the CNT/CCD (∼60 pA). Importantly, tertiapin-sensitive current was significantly higher in the DCT2/CNT than in the CNT/CCD (∼810 vs. ∼350 pA). We conclude that high ROMK activity in the DCT2/CNT is critical for aldosterone-independent renal K + secretion under baseline conditions. A low-K + diet significantly reduced ENaC but not ROMK activity in the DCT2/CNT. This suggests that modifying ENaC activity in the DCT2/CNT plays a key regulatory role in adjusting renal K + excretion to dietary K + intake. NEW & NOTEWORTHY ROMK-mediated renal K + secretion is essential for maintaining K + balance and requires a lumen negative transepithelial potential critically dependent on ENaC activity. Using microdissected distal mouse tubules, we demonstrated that baseline apical ROMK activity is high in the DCT2/CNT. Aldosterone-independent baseline ENaC activity is also high in the DCT2/CNT and downregulated by a low-K + diet, which highlights the important role of the DCT2/CNT in regulating K + secretion in an aldosterone-independent manner.

We used whole cell recording to examine the renal outer medullary K + channel (ROMK or Kir1.1) and epithelial Na + channel (ENaC) in the late distal convoluted tubule (DCT2)/initial connecting tubule ( i CNT) and in the cortical collecting duct (CCD) of kidney tubule-specific neural precursor cell-expressed developmentally downregulated protein 4-2 (Nedd4-2) knockout mice (Ks-Nedd4-2 KO) and floxed neural precursor cell-expressed developmentally downregulated 4-like ( Nedd4l ) mice (control). Tertiapin Q (TPNQ)-sensitive K + currents (ROMK) were smaller in both the DCT2/ i CNT and CCD of Ks-Nedd4-2 KO mice on a normal diet than in control mice. Neither high dietary salt intake nor low dietary salt intake had a significant effect on ROMK activity in the DCT2/ i CNT and CCD of control and Ks-Nedd4-2 KO mice. In contrast, high dietary K + intake (HK) increased, whereas low dietary K + intake (LK) decreased TPNQ-sensitive K + currents in floxed Nedd4l mice. However, the effects of dietary K + intake on ROMK channel activity were absent in Ks-Nedd4-2 KO mice since neither HK nor LK significantly affected TPNQ-sensitive K + currents in the DCT2/ i CNT and CCD. Moreover, TPNQ-sensitive K + currents in the DCT2/ i CNT and CCD of Ks-Nedd4-2 KO mice on HK were similar to those of control mice on LK. Amiloride-sensitive Na + currents in the DCT2/ i CNT and CCD were significantly higher in Ks-Nedd4-2 KO mice than in floxed Nedd4l mice on a normal K + diet. HK increased ENaC activity of the DCT2/ i CNT only in control mice, but HK stimulated ENaC of the CCD in both control and Ks-Nedd4-2 KO mice. Moreover, the HK-induced increase in amiloride-sensitive Na + currents was larger in Ks-Nedd4-2 KO mice than in control mice. Deletion of Nedd4-2 increased with no lysine kinase 1 expression and abolished HK-induced inhibition of with no lysine kinase 1. We conclude that deletion of Nedd4-2 increases ENaC activity but decreases ROMK activity in the aldosterone-sensitive distal nephron and that HK fails to stimulate ROMK, but robustly increases ENaC activity in the CCD of Nedd4-2-deficient mice. NEW & NOTEWORTHY We demonstrate that renal outer medullary K + (ROMK) channel activity is inhibited in the late distal convoluted tubule/initial connecting tubule and cortical collecting duct of neural precursor cell-expressed developmentally downregulated protein 4-2 (Nedd4-2)-deficient mice. Also, deletion of Nedd4-2 abolishes the stimulatory effect of dietary K + intake on ROMK. The lack of high K + -induced stimulation of ROMK is associated with the absence of high K + -induced inhibition of with no lysine kinase 1.

The physiological role of the shorter isoform of with no lysine kinase (WNK)1 that is exclusively expressed in the kidney (KS-WNK1), with particular abundance in the distal convoluted tubule, remains elusive. KS-WNK1, despite lacking the kinase domain, is nevertheless capable of stimulating the NaCl cotransporter, apparently through activation of WNK4. It has recently been shown that a less severe form of familial hyperkalemic hypertension featuring only hyperkalemia is caused by missense mutations in the WNK1 acidic domain that preferentially affect cullin 3 (CUL3)-Kelch-like protein 3 (KLHL3) E3-induced degradation of KS-WNK1 rather than that of full-length WNK1. Here, we show that full-length WNK1 is indeed less impacted by the CUL3-KLHL3 E3 ligase complex compared with KS-WNK1. We demonstrated that the unique 30-amino acid NH 2 -terminal fragment of KS-WNK1 is essential for its activating effect on the NaCl cotransporter and recognition by KLHL3. We identified specific amino acid residues in this region critical for the functional effect of KS-WNK1 and KLHL3 sensitivity. To further explore this, we generated KLHL3-R528H knockin mice that mimic human mutations causing familial hyperkalemic hypertension. These mice revealed that the KLHL3 mutation specifically increased expression of KS-WNK1 in the kidney. We also observed that in wild-type mice, the expression of KS-WNK1 was only detectable after exposure to a low-K + diet. These findings provide new insights into the regulation and function of KS-WNK1 by the CUL3-KLHL3 complex in the distal convoluted tubule and indicate that this pathway is regulated by dietary K + levels. NEW & NOTEWORTHY In this work, we demonstrated that the kidney-specific isoform of with no lysine kinase 1 (KS-WNK1) in the kidney is modulated by dietary K + and activity of the ubiquitin ligase protein Kelch-like protein 3. We analyzed the role of different amino acid residues of KS-WNK1 in its activity against the NaCl cotransporter and sensitivity to Kelch-like protein 3.

Phosphorylation of the thiazide-sensitive NaCl cotransporter (NCC) in the distal convoluted tubule (DCT) is altered rapidly in response to changes in extracellular K + concentration ([K + ]). High extracellular [K + ] is believed to activate specific phosphatases to dephosphorylate NCC, thereby reducing its activity. This process is defective in the human disease familial hyperkalemic hypertension, in which extracellular [K + ] fails to dephosphorylate NCC, suggesting an interplay between NCC-activating and NCC-inactivating switches. Here, we explored the role of STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) and intracellular Cl - concentration in the rapid effects of extracellular K + on NCC phosphorylation. SPAK was found to be rapidly dephosphorylated in vitro in human embryonic kidney cells and ex vivo in kidney slices by high [K + ]. Acute high-K + challenge resulted in DCT1-specific SPAK dephosphorylation in vivo and dissolution of SPAK puncta. In line with the postulate of interplay between activating and inactivating switches, we found that the "on" switch, represented by with no lysine kinase 4 (WNK4)-SPAK, must be turned off for rapid NCC dephosphorylation by high [K + ]. Longer-term WNK-SPAK-mediated stimulation, however, altered the sensitivity of the system, as it attenuated rapid NCC dephosphorylation due to acute K + loading. Although blockade of protein phosphatase (PP)1 increased NCC phosphorylation at baseline, neither PP1 nor PP3, singly or in combination, was essential for NCC dephosphorylation. Overall, our data suggest that NCC phosphorylation is regulated by a dynamic equilibrium between activating kinases and inactivating phosphatases, with kinase inactivation playing a key role in the rapid NCC dephosphorylation by high extracellular K + . NEW & NOTEWORTHY Although a great deal is known about mechanisms by which thiazide-sensitive NaCl cotransporter is phosphorylated and activated, much less is known about dephosphorylation. Here, we show that rapid dephosphorylation by high K + depends on the Cl - sensitivity of with no lysine kinase 4 and the rapid dephosphorylation of STE20/SPS1-related proline-alanine-rich protein kinase, primarily along the early distal convoluted tubule.

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 + (P K ) 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 P K is associated with nephrogenic DI (NDI), coincident with the development of altered AQP2 regulation, implicating low P K as a causal trigger of NDI. We found that P K 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 P K 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."

Our study provides novel findings of experimental hypokalemia reducing urea cycle functionality and thereby severely increasing plasma ammonia. This is pathophysiologically interesting because plasma ammonia increases during hypokalemia by a hitherto unknown mechanism, which may be particular important in relation to the unexplained link between hypokalemia and hepatic encephalopathy. Potassium deficiency decreases gene expression, protein synthesis, and growth. The urea cycle maintains body nitrogen homeostasis including removal of toxic ammonia. Hyperammonemia is an obligatory trait of liver failure, increasing the risk for hepatic encephalopathy, and hypokalemia is reported to increase ammonia. We aimed to clarify the effects of experimental hypokalemia on the in vivo capacity of the urea cycle, on the genes of the enzymes involved, and on ammonia concentrations. Female Wistar rats were fed a potassium-free diet for 13 days. Half of the rats were then potassium repleted. Both groups were compared with pair- and free-fed controls. The following were measured: in vivo capacity of urea-nitrogen synthesis (CUNS); gene expression (mRNA) of urea cycle enzymes; plasma potassium, sodium, and ammonia; intracellular potassium, sodium, and magnesium in liver, kidney, and muscle tissues; and liver sodium/potassium pumps. Liver histology was assessed. The diet induced hypokalemia of 1.9 ± 0.4 mmol/L. Compared with pair-fed controls, the in vivo CUNS was reduced by 34% ( P < 0.01), gene expression of argininosuccinate synthetase 1 ( ASS1 ) was decreased by 33% ( P < 0.05), and plasma ammonia concentrations were eightfold elevated ( P < 0.001). Kidney and muscle tissue potassium contents were markedly decreased but unchanged in liver tissue. Protein expressions of liver sodium/potassium pumps were unchanged. Repletion of potassium reverted all the changes. Hypokalemia decreased the capacity for urea synthesis via gene effects. The intervention led to marked hyperammonemia, quantitatively explainable by the compromised urea cycle. Our findings motivate clinical studies of patients with liver disease.

K + loading inhibits NKCC2 (Na-K-Cl cotransporter) and NCC (Na-Cl cotransporter) in the early distal tubules, resulting in Na + delivery to the late distal convoluted tubules (DCTs). In the DCTs, Na + entry through ENaC (epithelial Na channel) drives K + secretion through ROMK (renal outer medullary potassium channel). WNK4 (with-no-lysine 4) regulates the NCC/NKCC2 through SAPK (Ste20-related proline-alanine-rich kinase)/OSR1 (oxidative stress responsive). K + loading increases intracellular Cl - , which binds to the WNK4, thereby inhibiting autophosphorylation and downstream signals. Acute K + loading-deactivated NCC was not observed in Cl - -insensitive WNK4 mice, indicating that WNK4 was involved in K + loading-inhibited NCC activity. However, chronic K + loading deactivated NCC in Cl - -insensitive WNK4 mice, indicating that other mechanisms may be involved. We previously reported that mammalian Ste20-like protein kinase 3 (MST3/STK24) was expressed mainly in the medullary TAL (thick ascending tubule) and at lower levels in the DCTs. MST3 -/- mice exhibited higher ENaC activity, causing hypernatremia and hypertension. To investigate MST3 function in maintaining Na + /K + homeostasis in kidneys, mice were fed diets containing various concentrations of Na + and K + . The 2% KCl diets induced less MST3 expression in MST3 -/- mice than that in wild-type (WT) mice. The MST3 -/- mice had higher WNK4, NKCC2-S130 phosphorylation, and ENaC expression, resulting in lower urinary Na + and K + excretion than those of WT mice. Lower urinary Na + excretion was associated with elevated plasma [Na + ] and hypertension. These results suggest that MST3 maintains Na + /K + homeostasis in response to K + loading by regulation of WNK4 expression and NKCC2 and ENaC activity.

We examined the association between dietary potassium intake and all-cause and cause-specific mortality among community-dwelling older adults. Potassium intake was assessed with a food frequency questionnaire administered to 1,363 older adults (mean age 71.0 ± 10.6 years). Cox proportional hazard regressions estimated hazard ratios for sex-specific quintiles of calorie-adjusted potassium in relation to all-cause and cause-specific (cardiovascular disease, CVD, and stroke) mortality, adjusting for numerous covariates. There were 855 deaths (63% mortality) during the 20-year follow-up. Relative to the third quintile, potassium intake in the lowest quintile only was associated with increased risk of all-cause mortality (fully-adjusted hazard ratio 1.33; 95% CI 1.06, 1.67). Potassium intake was not significantly associated with CVD or stroke mortality. These results suggest that low potassium intake is associated with increased risk of mortality independent of overall health status. Ensuring adequate potassium in the diet may be an important strategy for reducing risk of earlier mortality among older adults.

This paper, for the first time, provides evidence that current practices that lead to agricultural crop removal of potassium are unsustainable and likely contributed to the decline in dietary potassium intake and rise in hypokalemia prevalence in the US population. Potassium concentrations in beef, pork, turkey, fruit, vegetables, cereal crops, and so forth decreased between 1999 and 2015 based on the examination of potassium values of food items of USDA standard reference. Ratios of potassium input to removal by crops between 1987 and 2014, potassium in topsoil, and crop-available soil potassium in US farms all declined in recent years. Reported reductions in dietary potassium intake correspond to these decreases in the food supply and to increases in hypokalemia prevalence in the US population. Results of this paper provide new understanding on links between potassium management in agricultural practices and potassium intake deficits, which is needed for combating increasing hypokalemia prevalence in the US population.

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.

The renal circadian clock has a major influence on the function of the kidney. Aryl hydrocarbon receptor nuclear translocator-like protein 1 [ARNTL; also known as brain and muscle ARNT-like 1 (BMAL1)] is a core clock protein and transcription factor that regulates the expression of nearly half of all genes. Using male and female kidney-specific cadherin BMAL1 knockout (KS-BMAL1 KO) mice, we examined the role of renal distal segment BMAL1 in blood pressure control and solute handling. We confirmed that this mouse model does not express BMAL1 in thick ascending limb, distal convoluted tubule, and collecting duct cells, which are the final locations for solute and fluid regulation. Male KS-BMAL1 KO mice displayed a substantially lower basal systolic blood pressure compared with littermate control mice, yet their circadian rhythm in pressure remained unchanged [male control mice: 127 ± 0.7 mmHg ( n = 4) vs. male KS-BMAL KO mice: 119 ± 2.3 mmHg ( n = 5), P < 0.05]. Female mice, however, did not display a genotype difference in basal systolic blood pressure [female control mice: 120 ± 1.6 mmHg ( n = 5) vs. female KS-BMAL1 KO mice: 119 ± 1.5 mmHg ( n = 7), P = 0.4]. In addition, male KS-BMAL1 KO mice had less Na + retention compared with control mice in response to a K + -restricted diet (15% less following 5 days of treatment). However, there was no genotype difference in Na + handling after a K + -restricted diet in female mice. Furthermore, there was evidence indicating a sex-specific response to K + restriction where female mice reabsorbed less Na + in response to this dietary challenge compared with male mice. We propose that BMAL1 in the distal nephron and collecting duct contributes to blood pressure regulation and Na + handling in a sex-specific manner.

Background: Potassium status has been found to affect glucose homeostasis., Objective: This study therefore aimed at investigating relationships between potassium status or dietary intake and fasting plasma glucose (FPG) or glycated haemoglobin (HbA1c) in a sample of Austrian adults (18-80 years, n = 421, 61% women) from the Austrian Study on Nutritional Status 2012., Methods: Dietary potassium intake was obtained by two 24 h recalls. FPG, plasma K+, and urinary K+ were determined photometrically, HbA1c by HPLC. Associations between the parameters were studied using multiple regression analysis after controlling for confounders and after age stratification of the sample (18-64 y vs. 65-80 y)., Results: Most of the participants had a potassium intake of less than the estimated adequate daily intake of 4000 mg/d. In the multiple regression analyses in the whole sample plasma K+ had a statistically significant positive effect on FPG only in the crude model (ß = 0.128, p < 0.01) and on HbA1c also in the fully adjusted model (ß = 0.129, p < 0.05). The small effects on HbA1c were also detected in the younger age group but were absent in the older population. However, in this latter, a reverse association of urinary K+ on HbA1c was observed as well as of dietary potassium intake on FPG with no effects in the younger sample., Conclusion: We suggest that age dependent differences in the association between parameters of potassium status and blood glucose regulation should also be taken into account., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The kidney needs to adapt daily to variable dietary K + contents via various mechanisms including diuretic, acid-base and hormonal changes that are still not fully understood. In this study, we demonstrate that following a K + -deficient diet in wildtype mice, the serine protease CAP2/Tmprss4 is upregulated in connecting tubule and cortical collecting duct and also localizes to the medulla and transitional epithelium of the papilla and minor calyx. Male CAP2/Tmprss4 knockout mice display altered water handling and urine osmolality, enhanced vasopressin response leading to upregulated adenylate cyclase 6 expression and cAMP overproduction, and subsequently greater aquaporin 2 (AQP2) and Na + -K + -2Cl - cotransporter 2 (NKCC2) expression following K + -deficient diet. Urinary acidification coincides with significantly increased H + ,K + -ATPase type 2 (HKA2) mRNA and protein expression, and decreased calcium and phosphate excretion. This is accompanied by increased glucocorticoid receptor (GR) protein levels and reduced 11β-hydroxysteroid dehydrogenase 2 activity in knockout mice. Strikingly, genetic nephron-specific deletion of GR leads to the mirrored phenotype of CAP2/Tmprss4 knockouts, including increased water intake and urine output, urinary alkalinisation, downregulation of HKA2, AQP2 and NKCC2. Collectively, our data unveil a novel role of the serine protease CAP2/Tmprss4 and GR on renal water handling upon dietary K + depletion.

Hyperkalemia and hyperphosphatemia are common metabolic disturbances in chronic kidney disease. Management may include instructions on a low-potassium or low-phosphorus diet, respectively. Low-phosphorus diet teaching includes information on phosphorus additives in addition to naturally occurring phosphorus food sources. Phosphorus additives are known to be more bioavailable compared with naturally occurring phosphorus. The concentration of phosphorus can also be much higher in processed foods compared with whole foods. Similar considerations may also be needed for dietary potassium teaching. The use of potassium additives in processed foods is growing, and when additives are used, the potassium concentration far exceeds naturally occurring potassium. Evidence also suggests, much like phosphate, potassium additives are more bioavailable than potassium found in whole foods. Clinicians and patients need to be aware of these changes in the food source to ensure potassium diet teaching is effective and safe., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Understanding measurement error in sodium and potassium intake is essential for assessing population intake and studying associations with health outcomes., Objective: The aim of this study was to compare sodium and potassium intake derived from 24-h dietary recall (24HDR) with intake derived from 24-h urinary excretion (24HUE)., Design: Data were analyzed from 776 nonpregnant, noninstitutionalized US adults aged 20-69 y who completed 1-to-2 24HUE and 24HDR measures in the 2014 NHANES. A total of 1190 urine specimens and 1414 dietary recalls were analyzed. Mean bias was estimated as mean of the differences between individual mean 24HDR and 24HUE measurements. Correlations and attenuation factors were estimated using the Kipnis joint-mixed effects model accounting for within-person day-to-day variability in sodium excretion. The attenuation factor reflects the degree to which true associations between long-term intake (estimated using 24HUEs) and a hypothetical health outcome would be approximated using a single 24HDR: values near 1 indicate close approximation and near 0 indicate bias toward null. Estimates are reported for sodium, potassium, and the sodium: potassium (Na/K) ratio. Model parameters can be used to estimate correlations/attenuation factors when multiple 24HDRs are available., Results: Overall, mean bias for sodium was -452 mg (95% CI: -646, -259), for potassium -315 mg (CI: -450, -179), and for the Na/K ratio -0.04 (CI: -0.15, 0.07, NS). Using 1 24HDR, the attenuation factor for sodium was 0.16 (CI: 0.09, 0.21), for potassium 0.25 (CI:0.16, 0.36), and for the Na/K ratio 0.20 (CI: 0.10, 0.25). The correlation for sodium was 0.27 (CI: 0.16, 0.37), for potassium 0.35 (CI: 0.26, 0.55), and for the Na/K ratio 0.27 (CI: 0.13, 0.32)., Conclusions: Compared with 24HUE, using 24HDR underestimates mean sodium and potassium intake but is unbiased for the Na/K ratio. Additionally, using 24HDR as a measure of exposure in observational studies attenuates the true associations of sodium and potassium intake with health outcomes., (Published by Oxford University Press on behalf of the American Society for Nutrition 2019.)

Tight regulation of K + balance is fundamental for normal physiology. Reduced dietary K + intake, which is common in Western diets, often leads to hypokalemia and associated cardiovascular- and kidney-related pathologies. The distal nephron, and, specifically, the collecting duct (CD), is the major site of controlled K + reabsorption via H + -K + -ATPase in the state of dietary K + deficiency. We (Mamenko MV, Boukelmoune N, Tomilin VN, Zaika OL, Jensen VB, O'Neil RG, Pochynyuk OM. Kidney Int 91: 1398-1409, 2017) have previously demonstrated that the transient receptor potential vanilloid type 4 (TRPV4) Ca 2+ channel, abundantly expressed in the CD, contributes to renal K + handling by promoting flow-induced K + secretion. Here, we investigated a potential role of TRPV4 in controlling H + -K + -ATPase-dependent K + reabsorption in the CD. Treatment with a K + -deficient diet (<0.01% K + ) for 7 days reduced serum K + levels in wild-type (WT) mice from 4.3 ± 0.2 to 3.3 ± 0.2 mM but not in TRPV4 -/- mice (4.3 ± 0.1 and 4.2 ± 0.3 mM, respectively). Furthermore, we detected a significant reduction in 24-h urinary K + levels in TRPV4 -/- compared with WT mice upon switching to K + -deficient diet. TRPV4 -/- animals also had significantly more acidic urine on a low-K + diet, but not on a regular (0.9% K + ) or high-K + (5% K + ) diet, which is consistent with increased H + -K + -ATPase activity. Moreover, we detected a greatly accelerated H + -K + -ATPase-dependent intracellular pH extrusion in freshly isolated CDs from TRPV4 -/- compared with WT mice fed a K + -deficient diet. Overall, our results demonstrate a novel kaliuretic role of TRPV4 by inhibiting H + -K + -ATPase-dependent K + reabsorption in the CD. We propose that TRPV4 inhibition could be a novel strategy to manage certain hypokalemic states in clinical settings.

Acute and chronic homeostatic pH regulation is critical for the maintenance of optimal cellular function. Renal mechanisms dominate global pH regulation over longer time frames, and rapid adjustments in ventilation compensate for acute pH and CO 2 changes. Ventilatory CO 2 and pH chemoreflexes are primarily determined by brain chemoreceptors with intrinsic pH sensitivity likely driven by K + channels. Here, we studied acute and chronic pH regulation in Kcnj16 mutant Dahl salt-sensitive (SS Kcnj16-/- ) rats; Kcnj16 encodes the pH-sensitive inwardly rectifying K + 5.1 (Kir5.1) channel. SS Kcnj16-/- rats hyperventilated at rest, likely compensating for a chronic metabolic acidosis. Despite their resting hyperventilation, SS Kcnj16-/- rats showed up to 45% reduction in the ventilatory response to graded hypercapnic acidosis vs. controls. SS Kcnj16-/- rats chronically treated with bicarbonate or the carbonic anhydrase inhibitor hydrochlorothiazide had partial restoration of arterial pH, but there was a further reduction in the ventilatory response to hypercapnic acidosis. SS Kcnj16-/- rats also had a nearly absent hypoxic ventilatory response, suggesting major contributions of Kir5.1 to O 2 - and CO 2 -dependent chemoreflexes. Although previous studies demonstrated beneficial effects of a high-K + diet (HKD) on cardiorenal phenotypes in SS Kcnj16-/- rats, HKD failed to restore the observed ventilatory phenotypes. We conclude that Kir5.1 is a key regulator of renal H + handling and essential for acute and chronic regulation of arterial pH as determinants of the ventilatory CO 2 chemoreflex.-Puissant, M. M., Muere, C., Levchenko, V., Manis, A. D., Martino, P., Forster, H. V., Palygin, O., Staruschenko, A., Hodges, M. R. Genetic mutation of Kcnj16 identifies Kir5.1-containing channels as key regulators of acute and chronic pH homeostasis.

BACKGROUND Dietary potassium has negative outcomes in patients with mildly impaired kidney function, while having positive outcomes in patients with hypertension. The association of dietary potassium intake with chronic kidney disease (CKD) development, with presence of hypertension, was studied in the Korean rural population with mildly impaired kidney function. MATERIAL AND METHODS From 3 rural areas of Korea, 5064 participants age ≥40 with CKD stage 2 at baseline were recruited. Patients were classified according to the quartile of dietary potassium intake. Newly developed CKD, defined as estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m² at the time of follow-up, and eGFR decline, defined as eGFR decrease >15% at follow-up, were studied. The effect of dietary potassium on CKD development and eGFR decline were studied by Cox proportional hazard models. The association of potassium with blood pressures and C-reactive protein was also studied to examine the underlying mechanisms. RESULTS Compared to 8.6% in normotensives, 15.7% of hypertensives developed CKD. The hazard ratio (HR) (95% confidence interval) of CKD was lower in high potassium diet only in hypertensives, with 0.60 (0.37-0.99) in the highest quartile. The eGFR decline was also lower in patients with higher potassium diet, with 0.70 (0.50-0.98) in Q3 and 0.54 (0.34-0.85) in Q4. Potassium intake has also been shown to decrease high diastolic blood pressure development (>90 mmHg) in hypertensives at 0.45 (0.25-0.83). CONCLUSIONS Dietary potassium was associated with lower risk of CKD development and eGFR decline, and this association was observed only in hypertensives.

Purpose of Review: Multiple clinical and translational evidence support benefits of high potassium diet; however, there many uncertainties underlying the molecular and cellular mechanisms determining effects of dietary potassium. Kir4.1 and Kir5.1 proteins form a functional heteromer (Kir4.1/Kir5.1), which is the primary inwardly rectifying potassium channel on the basolateral membrane of both distal convoluted tubule (DCT) and the collecting duct principal cells. The purpose of this mini-review is to summarize latest advances in our understanding of the evolution, physiological relevance and mechanisms controlling these channels., Recent Findings: Kir4.1 and Kir5.1 channels play a critical role in determining electrolyte homeostasis in the kidney and blood pressure, respectively. It was reported that Kir4.1/Kir5.1 serves as potassium sensors in the distal nephron responding to variations in dietary intake and hormonal stimuli. Global and kidney specific knockouts of either channel resulted in hypokalemia and severe cardiorenal phenotypes. Furthermore, knock out of Kir5.1 in Dahl salt-sensitive rat background revealed the crucial role of the Kir4.1/Kir5.1 channel in salt-induced hypertension., Summary: Here, we focus on reviewing novel experimental evidence of the physiological function, expression and hormonal regulation of renal basolateral inwardly rectifying potassium channels. Further investigation of molecular and cellular mechanisms controlling Kir4.1 and Kir4.1/Kir5.1-mediating pathways and development of specific compounds targeting these channels function is essential for proper control of electrolyte homeostasis and blood pressure.

G protein pathway suppressor 2 (GPS2) is a multifunctional protein and transcriptional regulation factor that is involved in the G protein MAPK signaling pathway. It has been shown that the MAPK signaling pathway plays an important role in the regulation of renal large-conductance Ca 2+ -activated potassium (BK) channels. In this study, we investigated the effects of GPS2 on BK channel activity and protein expression. In human embryonic kidney (HEK) BK stably expressing cells transfected with either GPS2 or its vector control, a single-cell recording showed that GPS2 significantly increased BK channel activity ( NP o ), increasing BK open probability ( P o ), and channel number ( N) compared with the control. In Cos-7 cells and HEK 293 T cells, GPS2 overexpression significantly enhanced the total protein expression of BK in a dose-dependent manner. Knockdown of GPS2 expression significantly decreased BK protein expression, while increasing ERK1/2 phosphorylation. Knockdown of ERK1/2 expression reversed the GPS2 siRNA-mediated inhibition of BK protein expression in Cos-7 cells. Pretreatments of Cos-7 cells with either the lysosomal inhibitor bafilomycin A1 or the proteasomal inhibitor MG132 partially reversed the inhibitory effects of GPS2 siRNA on BK protein expression. In addition, feeding a high-potassium diet significantly increased both GPS2 and BK protein abundance in mice. These data suggest that GPS2 enhances BK channel activity and its protein expression by reducing ERK1/2 signaling-mediated degradation of the channel.

With-no-lysine kinase 4 (WNK4) and kidney-specific (KS)-WNK1 regulate ROMK (Kir1.1) channels in a variety of cell models. We now explore the role of WNK4 and KS-WNK1 in regulating ROMK in the native distal convoluted tubule (DCT)/connecting tubule (CNT) by measuring tertiapin-Q (TPNQ; ROMK inhibitor)-sensitive K + currents with whole cell recording. TPNQ-sensitive K + currents in DCT2/CNT of KS- WNK1 -/- and WNK4 -/- mice were significantly smaller than that of WT mice. In contrast, the basolateral K + channels (a Kir4.1/5.1 heterotetramer) in the DCT were not inhibited. Moreover, WNK4 -/- mice were hypokalemic, while KS- WNK1 -/- mice had normal plasma K + levels. High K + (HK) intake significantly increased TPNQ-sensitive K + currents in DCT2/CNT of WT and WNK4 -/- mice but not in KS- WNK1 -/- mice. However, TPNQ-sensitive K + currents in the cortical collecting duct (CCD) were normal not only under control conditions but also significantly increased in response to HK in KS- WNK1 -/- mice. This suggests that the deletion of KS-WNK1-induced inhibition of ROMK occurs only in the DCT2/CNT. Renal clearance study further demonstrated that the deletion of KS-WNK1 did not affect the renal ability of K + excretion under control conditions and during increasing K + intake. Also, HK intake did not cause hyperkalemia in KS- WNK1 -/- mice. We conclude that KS-WNK1 but not WNK4 is required for HK intake-induced stimulation of ROMK activity in DCT2/CNT. However, KS-WNK1 is not essential for HK-induced stimulation of ROMK in the CCD, and the lack of KS-WNK1 does not affect net renal K + excretion.

The distal convoluted tubule (DCT) of the kidney plays an important role in blood pressure regulation by modulating Na + reabsorption via the Na + -Cl - cotransporter (NCC). A diet containing high salt (NaCl) and low K + activates NCC, thereby causing Na + retention and a rise in blood pressure. Since high blood pressure, hypertension, is associated with changes in serum calcium (Ca 2+ ) and magnesium (Mg 2+ ) levels, we hypothesized that dietary Na + and K + intake affects Ca 2+ and Mg 2+ transport in the DCT. Therefore, the present study aimed to investigate the effect of a high-Na + /low-K + diet on renal Ca 2+ and Mg 2+ handling. Mice were divided in four groups and fed a normal-Na + /normal-K + , normal-Na + /low-K + , high-Na + /normal-K + , or high-Na + /low-K + diet for 4 days. Serum and urine were collected for electrolyte and hormone analysis. Gene and protein expression of electrolyte transporters were assessed in kidney and intestine by qPCR and immunoblotting. Whereas Mg 2+ homeostasis was not affected, the mice had elevated urinary Ca 2+ and phosphate (P i ) excretion upon high Na + intake, as well as significantly lower serum Ca 2+ levels in the high-Na + /low-K + group. Alterations in the gene and protein expression of players involved in Ca 2+ and P i transport indicate that reabsorption in the proximal tubular and TAL is affected, while inducing a compensatory response in the DCT. These effects may contribute to the negative health impact of a high-salt diet, including kidney stone formation, chronic kidney disease, and loss of bone mineral density.

The Na + -Cl - cotransporter (NCC) in distal convoluted tubule (DCT) plays important roles in renal NaCl reabsorption. The current hypothesis for the mechanism of regulation of NCC focuses on WNK4 and intracellular Cl - concentration ([Cl - ] i ). WNK kinases bind Cl - , and Cl - binding decreases the catalytic activity. It is believed that hypokalemia under low K + intake decreases [Cl - ] i to activate WNK4, which thereby phosphorylates and stimulates NCC through activation of SPAK. However, increased NCC activity and apical NaCl entry would mitigate the fall in [Cl - ] i. Whether [Cl - ] i in DCT under low-K + diet is sufficiently low to activate WNK4 is unknown. Furthermore, increased luminal NaCl delivery also stimulates NCC and causes upregulation of the transporter. Unlike low K + intake, increased luminal NaCl delivery would tend to increase [Cl - ] i . Thus we investigated the role of WNK4 and [Cl - ] i in regulating NCC. We generated Wnk4-knockout mice and examined regulation of NCC by low K + intake and by increased luminal NaCl delivery in knockout (KO) and wild-type mice. Wnk4-KO mice have marked reduction in the abundance, phosphorylation, and functional activity of NCC vs. wild type. Low K + intake increases NCC phosphorylation and functional activity in wild-type mice, but not in Wnk4-KO mice. Increased luminal NaCl delivery similarly upregulates NCC, which, contrary to low K + intake, is not abolished in Wnk4-KO mice. The results reveal that modulation of WNK4 activity by [Cl - ] i is not the sole mechanism for regulating NCC. Increased luminal NaCl delivery upregulates NCC via yet unknown mechanism(s) that may override inhibition of WNK4 by high [Cl - ] i .

Background: Sodium-reduced packaged food products are increasingly available to consumers; however, it is not clear whether they are suitable for inclusion in a potassium-reduced diet. For individuals with impaired renal potassium excretion caused by chronic kidney disease and for those taking certain medications that interfere with the rennin-angiotensin aldosterone axis, the need to limit dietary potassium is important in view of the risk for development of hyperkalemia and fatal cardiac arrhythmias., Objective: The primary objective of this study was to determine the impact of the reduction of sodium in packaged meat and poultry products (MPPs) on the content of potassium and phosphorus from food additives., Design: This was a cross-sectional study comparing chemically analyzed MPPs (n=38, n=19 original, n=19 sodium-reduced), selected from the top three grocery chains in Canada, based on market share sales. All MPPs with a package label containing a reduced sodium content claim together with their non-sodium-reduced packaged MPP counterparts were selected for analysis. The protein, sodium, phosphorus, and potassium contents of sodium-reduced MPPs and the non-sodium-reduced (original) MPP counterparts were chemically analyzed according to the Association of Analytical Communities official methods 992.15 and 984.27 and compared by using a paired t test. The frequency of phosphorus and potassium additives appearing on the product labels' ingredient lists were compared between groups by using McNemar's test., Results: Sodium-reduced MPPs (n=19) contained 44% more potassium (mg/100 g) than their non-sodium-reduced counterparts (n=19) (mean difference [95% CI): 184 [90-279]; P=0.001). The potassium content of sodium-reduced MPPs varied widely and ranged from 210 to 1,500 mg/100 g. Potassium-containing additives were found on the ingredient list in 63% of the sodium-reduced products and 26% of the non-sodium-reduced products (P=0.02). Sodium-reduced MPPs contained 38% less sodium (mg/100 g) than their non-sodium-reduced counterparts (mean difference [95% CI]: 486 [334-638]; P<0.001). The amounts of phosphorus and protein, as well as the frequency of phosphorus additives appearing on the product label ingredient list, did not significantly differ between the two groups., Conclusions: Potassium additives are frequently added to sodium-reduced MPPs in amounts that significantly contribute to the potassium load for patients with impaired renal handling of potassium caused by chronic kidney disease and certain medications. Patients requiring potassium restriction should be counseled to be cautious regarding the potassium content of sodium-reduced MPPs and encouraged to make food choices accordingly., (Copyright © 2018 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Kir4.1 in the distal convoluted tubule plays a key role in sensing plasma potassium and in modulating the thiazide-sensitive sodium-chloride cotransporter (NCC). Here we tested whether dietary potassium intake modulates Kir4.1 and whether this is essential for mediating the effect of potassium diet on NCC. High potassium intake inhibited the basolateral 40 pS potassium channel (a Kir4.1/5.1 heterotetramer) in the distal convoluted tubule, decreased basolateral potassium conductance, and depolarized the distal convoluted tubule membrane in Kcnj10flox/flox mice, herein referred to as control mice. In contrast, low potassium intake activated Kir4.1, increased potassium currents, and hyperpolarized the distal convoluted tubule membrane. These effects of dietary potassium intake on the basolateral potassium conductance and membrane potential in the distal convoluted tubule were completely absent in inducible kidney-specific Kir4.1 knockout mice. Furthermore, high potassium intake decreased, whereas low potassium intake increased the abundance of NCC expression only in the control but not in kidney-specific Kir4.1 knockout mice. Renal clearance studies demonstrated that low potassium augmented, while high potassium diminished, hydrochlorothiazide-induced natriuresis in control mice. Disruption of Kir4.1 significantly increased basal urinary sodium excretion but it abolished the natriuretic effect of hydrochlorothiazide. Finally, hypokalemia and metabolic alkalosis in kidney-specific Kir4.1 knockout mice were exacerbated by potassium restriction and only partially corrected by a high-potassium diet. Thus, Kir4.1 plays an essential role in mediating the effect of dietary potassium intake on NCC activity and potassium homeostasis., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Available data indicate that dietary sodium (as salt) relates directly to blood pressure (BP). Most of these findings are from studies lacking dietary data; hence, it is unclear whether this sodium-BP relationship is modulated by other dietary factors. With control for multiple nondietary factors, but not body mass index, there were direct relations to BP of 24-hour urinary sodium excretion and the urinary sodium/potassium ratio among 4680 men and women 40 to 59 years of age (17 population samples in China, Japan, United Kingdom, and United States) in the INTERMAP (International Study on Macro/Micronutrients and Blood Pressure), and among its 2195 American participants, for example, 2 SD higher 24-hour urinary sodium excretion (118.7 mmol) associated with systolic BP 3.7 mm Hg higher. These sodium-BP relations persisted with control for 13 macronutrients, 12 vitamins, 7 minerals, and 18 amino acids, for both sex, older and younger, blacks, Hispanics, whites, and socioeconomic strata. With control for body mass index, sodium-BP-but not sodium/potassium-BP-relations were attenuated. Normal weight and obese participants manifested significant positive relations to BP of urinary sodium; relations were weaker for overweight people. At lower but not higher levels of 24-hour sodium excretion, potassium intake blunted the sodium-BP relation. The adverse association of dietary sodium with BP is minimally attenuated by other dietary constituents; these findings underscore the importance of reducing salt intake for the prevention and control of prehypertension and hypertension., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00005271., (© 2018 American Heart Association, Inc.)

We sought to decipher the mechanisms underlying the kidney's response to changes in K + load and intake, under physiological and pathophysiological conditions. To accomplish that goal, we applied a published computational model of epithelial transport along rat nephrons in a sham rat, an uninephrectomized (UNX) rat, and a 5/6-nephrectomized (5/6-NX) rat that also considers adaptations in glomerular filtration rate and tubular growth. Model simulations of an acute K + load indicate that elevated expression levels and activities of Na + /K + -ATPase, epithelial sodium channels, large-conductance Ca 2+ -activated K + channels, and renal outer medullary K + channels, together with downregulation of sodium-chloride cotransporters (NCC), increase K + secretion along the connecting tubule, resulting in a >6-fold increase in urinary K + excretion in sham rats, which substantially exceeds the filtered K + load. In the UNX and 5/6-NX models, the acute K + load is predicted to increase K + excretion, but at significantly reduced levels compared with sham. Acute K + load is accompanied by natriuresis in sham rats. Model simulations suggest that the lesser natriuretic effect observed in the nephrectomized groups may be explained by impaired NCC downregulation in these kidneys. At a single-nephron level, a high K + intake raises K + secretion along the connecting tubule and reabsorption along the collecting duct in sham, and even more in UNX and 5/6-NX. However, the increased K + secretion per tubule fails to sufficiently compensate for the reduction in nephron number, such that nephrectomized rats have an impaired ability to excrete an acute or chronic K + load.

Background: Dietary sodium and potassium affect the fluctuation in blood pressure (BP) and renal function. Corin, with its enzymatic activity to convert pro-atrial natriuretic peptide (pro-ANP) to biologically active ANP, regulates BP, cardiac, and renal functions. We investigated whether corin expression responds to a high-salt (HS) diet to regulate salt and water balance., Methods: Forty-two volunteers followed 3 sequential diets for 7 days each: a low-salt (LS) diet (3.0 g/day NaCl), a HS diet (18.0 g/day NaCl), followed by an HS diet with K+ supplementation (HS + K+) (18.0 g/day NaCl and 4.5 g/day KCl)., Results: Corin level was higher with the HS diet than the LS and HS + K+ diets and was positively correlated with systolic BP (SBP) and 24-hour urinary Na+ and microalbumin (U-mALB) excretion. In rodents, serum and renal levels of corin were transiently increased with the HS diet and were decreased if the HS diet was continued for up to 7 days. HS loading increased SBP, 24-hour urinary Na+, U-mALB excretion, and the expression of proprotein convertase subtilisin/kexin-6 (PCSK6), a corin activator. Knockdown of PCSK6 or corin in high salt-treated M1-cortical collecting duct (M1-CCD) cells increased the expression of aquaporin 2 (AQP2) and β-epithelial Na+ channel (β-ENaC)., Conclusions: Short-term HS may induce the PCSK6-corin-ANP-AQP2/β-ENaC pathway in the kidney. Enhanced serum corin level in humans and rodents is positively correlated with HS-induced SBP and 24-hour urinary Na+ and U-mALB excretion, which suggests that corin is involved in the salt-water balance in response to HS intake., Clinical Trials Registration: Public Trials Registry Number NCT02915315., (© American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

While much emphasis, and some controversy, centers on recommendations for sodium intake, there has been considerably less interest in recommendations for dietary potassium intake, in both the general population and patients with medical conditions, particularly acute and chronic kidney disease. Physiology literature and cohort studies have noted that the relative balance in sodium and potassium intakes is an important determinant of many of the sodium-related outcomes. A noteworthy characteristic of potassium in clinical medicine is the extreme concern shared by many practitioners when confronted by a patient with hyperkalemia. Fear of this often asymptomatic finding limits enthusiasm for recommending potassium intake and often limits the use of renin-angiotensin-aldosterone system blockers in patients with heart failure and chronic kidney diseases. New agents for managing hyperkalemia may alter the long-term management of heart failure and the hypertension, proteinuria, and further function loss in chronic kidney diseases. In this jointly sponsored effort between the American Society of Hypertension and the National Kidney Foundation, 3 panels of researchers and practitioners from various disciplines discussed and summarized current understanding of the role of potassium in health and disease, focusing on cardiovascular, nutritional, and kidney considerations associated with both hypo- and hyperkalemia., (Copyright © 2017 Published jointly in American Journal of Kidney Diseases and the Journal of the American society of Hypertension by Elsevier Inc, on behalf of the National Kidney Foundation and the American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

While much emphasis, and some controversy, centers on recommendations for sodium intake, there has been considerably less interest in recommendations for dietary potassium intake, in both the general population and patients with medical conditions, particularly acute and chronic kidney disease. Physiology literature and cohort studies have noted that the relative balance in sodium and potassium intakes is an important determinant of many of the sodium-related outcomes. A noteworthy characteristic of potassium in clinical medicine is the extreme concern shared by many practitioners when confronted by a patient with hyperkalemia. Fear of this often asymptomatic finding limits enthusiasm for recommending potassium intake and often limits the use of renin-angiotensin-aldosterone system blockers in patients with heart failure and chronic kidney diseases. New agents for managing hyperkalemia may alter the long-term management of heart failure and the hypertension, proteinuria, and further function loss in chronic kidney diseases. In this jointly sponsored effort between the American Society of Hypertension and the National Kidney Foundation, 3 panels of researchers and practitioners from various disciplines discussed and summarized current understanding of the role of potassium in health and disease, focusing on cardiovascular, nutritional, and kidney considerations associated with both hypo- and hyperkalemia., (Copyright © 2017 Journal of the American Society of Hypertension and American Journal of Kidney Disease. Published by Elsevier Inc. All rights reserved.)

Because of its cardio-protective effects, a low-Na, high-K diet (LNaHK) is often warranted in conjunction with diuretics to treat hypertensive patients. However, it is necessary to understand the renal handling of such diets in order to choose the best diuretic. Wild-type (WT) or Renal Outer Medullary K channel (ROMK) knockout mice (KO) were given a regular (CTRL), LNaHK, or high-K diet (HK) for 4-7 days. On LNaHK, mice treated with either IP furosemide for 12 hrs, or given furosemide in drinking water for 7 days, exhibited decreased K clearance. We used free-flow micropuncture to measure the [K + ] in the early distal tubule (EDT [K + ]) before and after furosemide treatment. Furosemide increased the EDT [K + ] in WT on CTRL but decreased that in WT on LNaHK. Furosemide did not affect the EDT [K + ] of KO on LNaHK or WT on HK. Furosemide-sensitive Na + excretion was significantly greater in mice on LNaHK than those on CTRL or HK. Patch clamp analysis of split-open TALs revealed that 70-pS ROMK exhibited a higher open probability (Po) but similar density in mice on LNaHK, compared with CTRL. No difference was found in the density or Po of the 30 pS K channels between the two groups. These results indicate mice on LNaHK exhibited furosemide-sensitive net K + secretion in the TAL that is dependent on increased NKCC2 activity and mediated by ROMK. We conclude that furosemide is a K-sparing diuretic by decreasing the TAL net K + secretion in subjects on LNaHK., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Disturbances of potassium homeostasis can cause either hyperkalemia or hypokalemia and result in serious consequences. Although the consequences of acute and chronic hyperkalemia and treatment of these conditions in CKD have been widely appreciated by nephrologists, more recent information has focused attention on the consequences of chronic hypokalemia. Several recent studies have documented a "U-shaped" relationship between the serum [K + ] and higher mortality in several clinical studies. The causes of dyskalemias are placed into the unique perspective of patients with CKD and its evolution with progression of CKD to later stages and focuses on the pathophysiology of these disorders. Emphasis is placed on the high mortality associated with both low and high levels of potassium that are unique to patients with CKD. Recent information regarding sensors of changes in the serum [K + ] that evoke changes in NaCl transport in the DCT1 and subsequent efferent responses by aldosterone-responsive cells in the DCT2 and cortical collecting duct to adjust K + secretion by the renal outer medullary potassium channel is reviewed in detail. These sensing mechanisms can be interrupted by drugs, such as the calcineurin inhibitors to cause both hypertension and hyperkalemia in kidney transplant patients, or can be inherited as familial hypertensive hyperkalemia. The role and pathogenesis of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in causing hyperkalemia is a common stop point for cessation of these important drugs, but, and newer agents to lower the serum [K + ] that might allow continuation of angiotensin-converting enzyme or angiotensin receptor blocker therapy are examined. Finally, the importance of emphasis on potassium-containing foods, such as fresh produce and fruit in the diets of patients with early-stage CKD, is examined as an under-appreciated area requiring more emphasis by nephrologists caring for these patients and may be unique to food-challenged patients with CKD., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

To maintain potassium homeostasis, kidneys exert flow-dependent potassium secretion to facilitate kaliuresis in response to elevated dietary potassium intake. This process involves stimulation of calcium-activated large conductance maxi-K (BK) channels in the distal nephron, namely the connecting tubule and the collecting duct. Recent evidence suggests that the TRPV4 channel is a critical determinant of flow-dependent intracellular calcium elevations in these segments of the renal tubule. Here, we demonstrate that elevated dietary potassium intake (five percent potassium) increases renal TRPV4 mRNA and protein levels in an aldosterone-dependent manner and causes redistribution of the channel to the apical plasma membrane in native collecting duct cells. This, in turn, leads to augmented TRPV4-mediated flow-dependent calcium ion responses in freshly isolated split-opened collecting ducts from mice fed the high potassium diet. Genetic TRPV4 ablation greatly diminished BK channel activity in collecting duct cells pointing to a reduced capacity to excrete potassium. Consistently, elevated potassium intake induced hyperkalemia in TRPV4 knockout mice due to deficient renal potassium excretion. Thus, regulation of TRPV4 activity in the distal nephron by dietary potassium is an indispensable component of whole body potassium balance., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Mice transgenic for genomic segments harboring PHAII (pseudohypoaldosteronism type II) mutant Wnk4 (with-No-Lysine kinase 4) (TgWnk4 PHAII ) have hyperkalemia which is currently believed to be the result of high activity of Na-Cl cotransporter (NCC). This leads to decreasing Na + delivery to the distal nephron segment including late distal convoluted tubule (DCT) and connecting tubule (CNT). Since epithelial Na + channel (ENaC) and renal outer medullary K + channel (ROMK or Kir4.1) are expressed in the late DCT and play an important role in mediating K + secretion, the aim of the present study is to test whether ROMK and ENaC activity in the DCT/CNT are also compromised in the mice expressing PHAII mutant Wnk4. Western blot analysis shows that the expression of βENaC and γENaC subunits but not αENaC subunit was lower in TgWnk4 PHAII mice than that in wild-type (WT) and TgWnk4 WT mice. Patch-clamp experiments detected amiloride-sensitive Na + currents and TPNQ-sensitive K + currents in DCT2/CNT, suggesting the activity of ENaC and ROMK. However, both Na + and ROMK currents in DCT2/CNT of TgWnk4 PHAII mice were significantly smaller than those in WT and TgWnk4 WT mice. In contrast, the basolateral K + currents in the DCT were similar among three groups, despite higher NCC expression in TgWnk4 PHAII mice than those of WT and TgWnk4 WT mice. An increase in dietary K + intake significantly increased both ENaC and ROMK currents in the DCT2/CNT of all three groups. However, high-K + (HK) intake-induced stimulation of Na + and K + currents was smaller in TgWnk4 PHAII mice than those in WT and TgWnk4 WT mice. We conclude that ENaC and ROMK channel activity in DCT2/CNT are inhibited in TgWnk4 PHAII mice and that Wnk4 PHAII -induced inhibition of ENaC and ROMK may contribute to the suppression of K + secretion in the DCT2/CNT in addition to increased NCC activity., (Copyright © 2017 the American Physiological Society.)