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Published in final edited form as: Curr Opin Pharmacol. 2013 Dec 11;0:28–32. doi: 10.1016/j.coph.2013.11.001

Interacting influence of diuretics and diet on BK channel-regulated K homeostasis

Donghai Wen 1, Ryan J Cornelius 1, Steven C Sansom 1
PMCID: PMC3984455  NIHMSID: NIHMS546125  PMID: 24721651

Abstract

Large conductance, Ca-activated K channels are abundantly located in cells of vasculature, glomerulus and distal nephron, where they are involved in maintaining blood volume, blood pressure and K homeostasis. In mesangial cells and smooth muscle cells of vessels, the BK-α pore associates with BK-β1 subunits and regulates contraction in a Ca-mediated feedback manner. The BK-β1 also resides in connecting tubule cells of the nephron. BK-β1 knockout mice (β1KO) exhibit fluid retention, hypertension, and compromised K handling. The BK-α/β4resides in acid/base transporting intercalated cells (IC) of the distal nephron, where they mediate K secretion in mammals on a high K, alkaline diet. BK-α expression in IC is increased by a high K diet via aldosterone. The BK-β4 subunit and alkaline urine are necessary for the luminal expression and function of BK-α in mouse IC. In distal nephron cells, membrane BK-α expression is inhibited by WNK4 in in vitro expression systems, indicating a role in the hyperkalemic phenotype in patients with familial hyperkalemic hypertension type 2 (FHHt2). β1KO and BK-β4 knockout mice (β4KO) are hypertensive because of exaggerated ENaC-mediated Na retention in an effort to secrete K via only ROMK. BK hypertension is resistant to thiazides and furosemide, and would be more amenable to ENaC and aldosterone inhibiting drugs. Activators of BK-α/β1 or BK-α/β4 might be effective blood pressure lowering agents for a subset of hypertensive patients. Inhibitors of renal BK would effectively spare K in patients with Bartter Syndrome, a renal K wasting disease.

Introduction

Large conductance, Ca-activated K channels (BK), are localized in a variety of kidney cells, where they have far-ranging roles from regulators of glomerular filtration to conduits for potassium secretion. Previous reviews have summarized the topic of BK as a K secretory channel [1-4]. This review will emphasize studies of BK in the kidney with respect to diuretics, diet and pathological conditions. Our understanding of BK-mediated K secretion has advanced markedly in recent years due to studies with genetically altered mice. For several years, the renal outer medullary K channel (ROMK) has been the most extensively studied K secretory channel because of its localization in principal cells of the cortical collecting duct and its high open probability at resting membrane potentials. However, either ROMK or BK may be the predominating K secretory channel, depending on the dietary conditions [1].

Because plasma [K] must be regulated within very narrow limits, it is not surprising that redundancies for eliminating K have evolved. Either ROMK or BK knockout mice exhibit minimal problems and maintain K homeostasis when consuming a normal K diet. However renal responsiveness to consuming a high K, alkaline diet is seriously impaired in BK-β4 knockout mice (β4KO) and their plasma [K] increases markedly. Therefore, BK is probably the “ancient” channel, shown to secrete K in the mammalian gastrointestinal tract [5], amphibian kidneys [6], and in mammals on a high K, alkaline diet [7].

Several studies have shown the health benefits of the “Mediterranean” or “Paleolithic” diet, which consists of fruits and vegetables and is alkaline [8-10]. It is important to determine how K is handled with the ancient diet and determine whether the old standards for diuretic therapy and K homeostasis still apply. The increasing number of individuals now on ancient diets may experience dangerous elevations in plasma [K] levels when given the most popular diuretic agents that normally reduce plasma [K] of those on the “Western” acidic diets.

Localization of BK in the kidney

All smooth muscle cells, including those of the renal vessels [11-13], contain BK. Because of inaccessibility to patch clamping, BK have been difficult to identify and study in vivo or in isolated glomerular cells. However, BK have been studied in detail in cultured podocytes [14] and mesangial cells [15;16], where they are abundantly expressed.

Before BK were immunologically identified in specific renal segments, they were identified at the apical membrane of rabbit and rat cortical collecting ducts (CCD) using patch clamping [17;18]. Perfusion of isolated collecting ducts revealed that iberiotoxin, a specific pharmacological blocker of BK, could inhibit K secretion during high tubular fluid flows [19].

The pore-forming BK-α was found most abundantly within the acid/base transporting intercalated cells (IC) of the CNT and collecting duct by both patch clamping [20] and immunohistochemical staining (IHC) [21] (see figure 1). In the medullary collecting duct (MCD), BK-α appears mostly peri-nuclear in PC and IC [21].

Figure 1.

Figure 1

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IHC of BK-α in cortical collecting ducts revealing cytosolic vs apical expression in WT and β4KO on control, HK-alk and HK-Cl diet. BK-α resides in the apical membrane only in WT on HK-alk diet.

In all cells where BK is expressed, one of four beta subunits (BK-β1-4) is associated with the pore-forming BK-α. The different BK subunits modify the BK-α properties in different ways. Three of the four BK subunits (BK-β1, β2, and β4) have been identified by Western blot of mouse kidney [22] and RT-PCR of isolated rat CCDs [23]. IHC subsequently localized the BK-β1 to the apical membrane of the mouse CNT and the CNT and initial CCD of the rabbit [24]. IHC has yet to identify the localization of BK-β3. IC in vivo [22;25] and the IC cell line, MDCK-C11, exhibit an abundance of BK-α and BK-β4 by RT-PCR, Western blot and IHC [26].

Regulation of BK in the kidney

Two major kinase systems, the aldosterone-induced serum and glucocorticoid kinase (SGK) system, which regulates the ENaC-mediated Na reabsorption in exchange for either K or H secretion, and the with no lysine kinase (WNK) system, which regulates NKCC and NCC in the thick ascending limb and early distal tubule, have emerged as two primary signaling networks governing Na and K homeostasis in the kidneys.

Aldosterone

A high K diet increases plasma [K], which stimulates the production of aldosterone, yielding increased total cellular, but not surface, BK-α expression in the kidney [21;27]. Aldosterone similarly increases BK-α expression in the colon [28]. An alkaline luminal fluid enhances expression of BK-β4, which promotes apical localization of BK-α in IC, possibly by inhibiting its degradation through the lysosomal pathway [21]. At the same time, aldosterone also enhances the driving force for K secretion by increasing ENaC and Na-K-ATPase-mediated Na reabsorption in PC [29;30] (see Figs 1 and 2).

Figure 2. Regulation of BK-α/β4 in kidney.

Figure 2

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Urinary pH regulates BK-β4 expression. Plasma aldosterone (Aldo) binds to the mineralocorticoid receptor (MR), which increases BK-α transcription and expression. BK-β4 stabilizes BK-α expression at the apical membrane of IC by inhibiting the degradation via lysosomal/proteosomal pathway, while WNK4/SPAK kinase system promotes it.

WNK4-SPAK system

Aldosterone can be secreted from the adrenal glomerulosa in response to high plasma [K] or to low Na intake that activates the renin-angiotensin II (ANGII) axis. The low Na axis results in increased NCC-mediated Na reabsorption in the DCT and the high plasma [K] axis increases ROMK-mediated K secretion in exchange for ENaC-mediated Na reabsorption in the CNT and initial cortical collecting duct. The difference between the two actions of aldosterone is the compounded effects of high ANGII, in the case of low Na axis, which acts through a WNK4-SPAK kinase system, to promote the incorporation of NCC into the luminal membrane [31-33].

A common mutation of WNK4 renders exaggerated Na and Cl reabsorption and K retention, a disease known as familial hyperkalemic hypertension (FHHt) [34]. The hyperkalemia of FHHt indicates that WNK4 may also directly inhibit K channel mediated K secretion in the CNT and CCD. Expressing BK-α in HEK-293 cells showed that WNK4 inhibits BK activity by enhancing its ubiquitinization and degradation [35] or via the MAPK pathway [36], which inhibits BK expression in the principal cells of the rat cortical collecting duct [35]. Zhuang et al also showed that WNK4 led to the degradation of BK-α in HEK-293 cells through the lysosomal pathway [37].

A variety of other signaling networks seem to converge on BK in the CCD; however the relevance is still uncertain in most cases. Urinary carbon monoxide activates BK in the CCD through a nitric oxide-cGMP-independent pathway [38]. Nitric oxide stimulates, while reactive oxygen species inhibits BK in the renal artery [12]. Epoxyeicosatrienoic acid (EET) activates [39] BK in the CCD and prostaglandin E2 (PGE2) inhibits BK in the CCD through the MAPK pathway [40]. Protein kinases A and C may also regulate BK in the CCD [41].

BK in hypertension and disease

Knockouts of the BK-β1 subunit (β1KO) are hypertensive [42-45] and exhibit cardiac hypertrophy when consuming a high K diet for only 7-10 days [2]. The BK-β1 associates with the BK-α in all smooth muscle cells, where it increases the sensitivity of the BK-α to Ca, an effect that increases its action as a feedback regulator of contraction. The absence of BK-β1 diminishes coupling of BK to Ca sparks, which enhances vessel tone [46] and results in an elevation of mean arterial pressure (MAP) by about 15 mm Hg above normal. Although BK are localized in renal vessels, results indicate that these BK do not play a significant role as feedback regulators of renal blood flow in response to angiotensin II, norepinephrine or vasopressin [13;47]. Therefore, β1KO hypertension is partly due to a global increase in blood vessel tone and not the result of impaired regulation of renal blood flow.

Further analysis of mice renal function using metabolic cages revealed that the hypertension of β1KO was exacerbated by a high K diet and was the result of fluid accumulation and aldosteronism due to the failure to eliminate K [44]. The hypertension of β1KO on a high K diet was very responsive to eplerenone, which inhibits aldosterone receptors [44]. On a high K diet, the fluid retention was completely eliminated by eplerenone, but significant hypertension of about 8 mmHg remained, indicating a combination of vascular tone and fluid accumulation effects.

Knockouts of the BK-β4 subunit (β4KO) also exhibit fluid retention and hypertension on a high K diet; however, the hypertension is milder than that of β1KO, probably because the vascular component is not involved in the hypertension [2]. The results of these studies highlight the hypertensive consequences of the failure to eliminate K appropriately when consuming a high K diet.

The hypertension described for BK-α knockouts, BK-α-KO, β1KO and β4KO is mild and probably would only be obvious in humans on a high K diet. A population of BK mutations on a high K diet would be difficult to detect. However, there are reports of hypertensive patients who have aldosteronism and are resistant to all diuretic therapy except for aldosterone receptor blockers [48], which would attenuate the Na retention by ENaC that is attempting to compensate for the failure of BK-mediated K secretion by the less efficient Na for K exchange in PC. Several studies have revealed an association between single nucleotide polymorphisms (SNPs) in BK-β1 and hypertension [49-51]. It would be interesting to determine whether a population of hypertensive individuals (with high plasma [K] and aldosteronism) has specific mutations in BK-β1.

BK-mediated K excretion with diuretics and salt-wasting disorders

The relevance of the BK-α/β4 is best demonstrated by animals placed on a low Na, high K, alkaline diet (LNaHK-alk), which mimics the diet of ancient man and the present-day Yanomami of South America [52]. On a normal diet, Na is reabsorbed via ENaC in exchange for K secretion via ROMK in the PC without requiring alkalinity to maintain normal plasma K. However, when dietary Na is very low and the K is high, the exchange requires alkalinity and the BK-α/β4 to eliminate the K (D Wen et al., unpublished). In β4KO mice, compared with wild type (WT), on a low Na, high K, alkaline diet, the capacity to secrete K is diminished considerably, while the ability to reabsorb Na is intact or enhanced. However, the high capacity of WT to secrete K on LNaHK is still linked to ENaC-mediated Na reabsorption. Therefore, BK-α/β4 has a role to enhance the coupling of K secreted per Na reabsorbed when given the LNaHK, alkaline diet. Except for the fact that both pendrin-mediated HCO3 secretion and BK-α/β4-mediated K secretion are located on the apical membrane of IC, the mechanism is not understood.

A high K diet enhances urinary flow in mice by more than 5-fold [7]. High flow increases BK-α/β4 channel activity in IC, partially by releasing urine ATP [53;54]. The increased luminal volume dilutes the K in the CCD in order to maintain a chemical secretory gradient. Flow is increased by K recycling, which ensures a high medullary K concentration that inhibits Na reabsorption in the thick ascending limb [55].

The natural mechanism to eliminate K by high flow is mimicked by blood pressure lowering agents, such as furosemide and hydrochlorothiazde, which inhibit Na reabsorption by NKCC of the thick ascending limb and the NCC of the early distal tubule, respectively. As expected, a complicating side effect of such diuretics is kaliuresis and hypokalemia due to the increased volume to the aldosterone sensitive distal nephron (ASDN). Moreover, the loss of Na and body fluids increases aldosterone, which enhances expression of ENaC and Na-K-ATPase, increasing Na for K exchange.

Potassium is often supplemented with diuretics in order to prevent hypokalemia. However, the dogma of K loss with a diuretic would not apply for some popular vegetarian diets, which are low in Na, high in K and alkaline. Thiazides will be less effective diuretics because the NCC-mediated Na reabsorption is overshadowed by ENaC-mediated Na reabsorption in order to eliminate K. Moreover, a high K intake may turn off WNK4-regulated NCC in favor of ENaC-mediated Na for K exchange [56]. More severe problems could occur with furosemide. Animals on a high K diet may utilize the NKCC1 on the basolateral membrane of the collecting duct IC to extrude K [57]. Thus, furosemide could cause hyperkalemia in patients on an ancient diet instead of the usual hypokalemic response afforded to patients on an acidic, high Na diet.

Two genetic disorders, Bartter Syndrome, a defect of Na reabsorption in the thick ascending limb, and Gitelman Syndrome, a defect of Na reabsorption by the NCC of the early distal tubule, are often associated with severe K wasting because of high volumes delivered to the aldosterone-sensitive distal nephron that stimulate BK-mediated K secretion. Bartter and Gitelman syndromes are the genetic equivalents to administering furosemide and thiazides, respectively. For these conditions, a specific inhibitor of renal BK-α/β4 should prevent K wasting. However, BK inhibitors such as paxilline and Iberiotoxin would have profound global effects on all BK channels.

Highlights.

  • BK are expressed in the cells of vasculature, glomerulus, and distal nephron.

  • BK mediate K secretion when consuming a low Na, high K, alkaline diet.

  • BK are regulated by aldosterone/SGK and WNK4/SPAK pathways in the kidney.

  • BK deficiency is related to hypertension.

  • Results of diuretic therapy are altered by BK-mediated K secretion.

Footnotes

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Reference List

  • 1.Sansom SC, Welling PA. Two channels for one job. Kidney Int. 2007;72:529–530. doi: 10.1038/sj.ki.5002438. [DOI] [PubMed] [Google Scholar]
  • 2.Holtzclaw JD, Grimm PR, Sansom SC. Role of BK channels in hypertension and potassium secretion. Curr.Opin.Nephrol.Hypertens. 2011;20:512–517. doi: 10.1097/MNH.0b013e3283488889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Rodan AR, Huang CL. Distal potassium handling based on flow modulation of maxi-K channel activity. Curr.Opin.Nephrol.Hypertens. 2009;18:350–355. doi: 10.1097/MNH.0b013e32832c75d8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Pluznick JL, Sansom SC. BK channels in the kidney: role in K(+) secretion and localization of molecular components. Am J Physiol Renal Physiol. 2006;291:F517–F529. doi: 10.1152/ajprenal.00118.2006. [DOI] [PubMed] [Google Scholar]
  • 5.Sorensen MV, Matos JE, Praetorius HA, Leipziger J. Colonic potassium handling. Pflugers Arch. 2010;459:645–656. doi: 10.1007/s00424-009-0781-9. [DOI] [PubMed] [Google Scholar]
  • 6.Stoner LC, Viggiano SC. Environmental KCl causes an upregulation of apical membrane maxi K and ENaC channels in everted Ambystoma collecting tubule. J Membr.Biol. 1998;162:107–116. doi: 10.1007/s002329900348. [DOI] [PubMed] [Google Scholar]
  • **7.Cornelius RJ, Wen D, Hatcher LI, Sansom SC. Bicarbonate promotes BK-alpha/beta4-mediated K excretion in the renal distal nephron. Am.J.Physiol Renal Physiol. 2012;303:F1563–F1571. doi: 10.1152/ajprenal.00490.2012. First study to reveal that an alkaline, high K diet was dependent on BK-β4 subunit to maintain K homeostasis in mice.
  • 8.Panagiotakos DB, Matalas AL. Back to the ancient diet: a matter of urgency for Southern Mediterranean countries. Nutr.Metab Cardiovasc.Dis. 2009;19:153–155. doi: 10.1016/j.numecd.2009.02.001. [DOI] [PubMed] [Google Scholar]
  • 9.Keys A, Menotti A, Karvonen MJ, Aravanis C, Blackburn H, Buzina R, Djordjevic BS, Dontas AS, Fidanza F, Keys MH. The diet and 15-year death rate in the seven countries study. Am.J.Epidemiol. 1986;124:903–915. doi: 10.1093/oxfordjournals.aje.a114480. [DOI] [PubMed] [Google Scholar]
  • 10.Trichopoulou A, Costacou T, Bamia C, Trichopoulos D. Adherence to a Mediterranean diet and survival in a Greek population. N.Engl.J.Med. 2003;348:2599–2608. doi: 10.1056/NEJMoa025039. [DOI] [PubMed] [Google Scholar]
  • 11.Stockand JD, Sansom SC. Potassium channels in the renal circulation. In: Archer SL, Rusch NJ, editors. Potassium channels in cardiovascular biology. edn 1. Kluwer Academic/Plenum; New York: 2001. pp. 571–589. [Google Scholar]
  • 12.Brakemeier S, Eichler I, Knorr A, Fassheber T, Kohler R, Hoyer J. Modulation of Ca2+-activated K+ channel in renal artery endothelium in situ by nitric oxide and reactive oxygen species. Kidney Int. 2003;64:199–207. doi: 10.1046/j.1523-1755.2003.00051.x. [DOI] [PubMed] [Google Scholar]
  • 13.Magnusson L, Sorensen CM, Braunstein TH, Holstein-Rathlou NH, Salomonsson M. Renovascular BK(Ca) channels are not activated in vivo under resting conditions and during agonist stimulation. Am.J.Physiol Regul.Integr.Comp Physiol. 2007;292:R345–R353. doi: 10.1152/ajpregu.00337.2006. [DOI] [PubMed] [Google Scholar]
  • 14.Zhang R, Sun H, Liao C, Yang H, Zhao B, Tian J, Dong S, Zhang Z, Jiao J. Chronic hypoxia in cultured human podocytes inhibits BKCa channels by upregulating its beta4-subunit. Biochem.Biophys.Res.Commun. 2012;420:505–510. doi: 10.1016/j.bbrc.2012.03.021. [DOI] [PubMed] [Google Scholar]
  • 15.Stockand JD, Sansom SC. Large Ca2+-activated K+ channels responsive to angiotensin II in cultured human mesangial cells. Am.J.Physiol.Cell Physiol. 1994;267:C1080–C1086. doi: 10.1152/ajpcell.1994.267.4.C1080. [DOI] [PubMed] [Google Scholar]
  • 16.Stockand JD, Sansom SC. Glomerular mesangial cells: electrophysiology and regulation of contraction. Physiol Rev. 1998;78:723–744. doi: 10.1152/physrev.1998.78.3.723. [DOI] [PubMed] [Google Scholar]
  • 17.Taniguchi J, Imai M. Flow-dependent activation of maxi K+ channels in apical membrane of rabbit connecting tubule. J.Membr.Biol. 1998;164:35–45. doi: 10.1007/s002329900391. [DOI] [PubMed] [Google Scholar]
  • 18.Frindt G, Palmer LG. Apical potassium channels in the rat connecting tubule. Am J Physiol Renal Physiol. 2004;287:F1030–F1037. doi: 10.1152/ajprenal.00169.2004. [DOI] [PubMed] [Google Scholar]
  • 19.Woda CB, Bragin A, Kleyman TR, Satlin LM. Flow-dependent K+ secretion in the cortical collecting duct is mediated by a maxi-K channel. Am.J.Physiol Renal Physiol. 2001;280:F786–F793. doi: 10.1152/ajprenal.2001.280.5.F786. [DOI] [PubMed] [Google Scholar]
  • 20.Palmer LG, Frindt G. High-conductance K channels in intercalated cells of the rat distal nephron. Am J Physiol Renal Physiol. 2006 doi: 10.1152/ajprenal.00191.2006. [DOI] [PubMed] [Google Scholar]
  • **21.Wen D, Cornelius RJ, Yuan Y, Sansom SC. Regulation of BK-alpha expression in the distal nephron by aldosterone and urine pH. Am.J.Physiol Renal Physiol. 2013;305:F463–F476. doi: 10.1152/ajprenal.00171.2013. Study showed that BK-β4 and alkaline urine is required for expression of BK-α in the apical membrane of intercalated cells of mice.
  • 22.Grimm PR, Foutz RM, Brenner R, Sansom SC. Identification and localization of BK-beta subunits in the distal nephron of the mouse kidney. Am.J.Physiol Renal Physiol. 2007;293:F350–F359. doi: 10.1152/ajprenal.00018.2007. [DOI] [PubMed] [Google Scholar]
  • 23.Najjar F, Zhou H, Morimoto T, Bruns JB, Li HS, Liu W, Kleyman TR, Satlin LM. Dietary K+ regulates apical membrane expression of maxi-K channels in rabbit cortical collecting duct. Am J Physiol Renal Physiol. 2005;289:F922–F932. doi: 10.1152/ajprenal.00057.2005. [DOI] [PubMed] [Google Scholar]
  • 24.Pluznick JL, Wei P, Grimm PR, Sansom SC. BK-{beta}1 subunit: immunolocalization in the mammalian connecting tubule and its role in the kaliuretic response to volume expansion. Am J Physiol Renal Physiol. 2005;288:F846–F854. doi: 10.1152/ajprenal.00340.2004. [DOI] [PubMed] [Google Scholar]
  • 25.Holtzclaw JD, Grimm PR, Sansom SC. Intercalated cell BK-alpha/beta4 channels modulate sodium and potassium handling during potassium adaptation. J.Am.Soc.Nephrol. 2010;21:634–645. doi: 10.1681/ASN.2009080817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Holtzclaw JD, Liu L, Grimm PR, Sansom SC. Shear stress-induced volume decrease in C11-MDCK cells by BK-{alpha}/{beta}4. Am.J.Physiol Renal Physiol. 2010;299:F507–F516. doi: 10.1152/ajprenal.00222.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Estilo G, Liu W, Pastor-Soler N, Mitchell P, Carattino MD, Kleyman TR, Satlin LM. Effect of aldosterone on BK channel expression in mammalian cortical collecting duct. Am.J.Physiol Renal Physiol. 2008;295:F780–F788. doi: 10.1152/ajprenal.00002.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Sorensen MV, Matos JE, Sausbier M, Sausbier U, Ruth P, Praetorius HA, Leipziger J. Aldosterone increases KCa1.1 (BK) channel-mediated colonic K+ secretion. J.Physiol. 2008;586:4251–4264. doi: 10.1113/jphysiol.2008.156968. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Verrey F, Summa V, Heitzmann D, Mordasini D, Vandewalle A, Feraille E, Zecevic M. Short-term aldosterone action on Na,K-ATPase surface expression: role of aldosterone-induced SGK1? Ann.N.Y.Acad.Sci. 2003;986:554–561. doi: 10.1111/j.1749-6632.2003.tb07253.x. [DOI] [PubMed] [Google Scholar]
  • 30.Verrey F. Sodium reabsorption in aldosterone-sensitive distal nephron: news and contributions from genetically engineered animals. Curr.Opin.Nephrol.Hypertens. 2001;10:39–47. doi: 10.1097/00041552-200101000-00007. [DOI] [PubMed] [Google Scholar]
  • 31.Sandberg MB, Riquier AD, Pihakaski-Maunsbach K, McDonough AA, Maunsbach AB. ANG II provokes acute trafficking of distal tubule Na+-Cl(−) cotransporter to apical membrane. Am.J.Physiol Renal Physiol. 2007;293:F662–F669. doi: 10.1152/ajprenal.00064.2007. [DOI] [PubMed] [Google Scholar]
  • 32.Castaneda-Bueno M, Cervantes-Perez LG, Vazquez N, Uribe N, Kantesaria S, Morla L, Bobadilla NA, Doucet A, Alessi DR, Gamba G. Activation of the renal Na+:Cl− cotransporter by angiotensin II is a WNK4-dependent process. Proc.Natl.Acad.Sci.U.S.A. 2012;109:7929–7934. doi: 10.1073/pnas.1200947109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.van der Lubbe N, Lim CH, Fenton RA, Meima ME, Jan Danser AH, Zietse R, Hoorn EJ. Angiotensin II induces phosphorylation of the thiazide-sensitive sodium chloride cotransporter independent of aldosterone. Kidney Int. 2011;79:66–76. doi: 10.1038/ki.2010.290. [DOI] [PubMed] [Google Scholar]
  • 34.Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension. Cell. 2001;104:545–556. doi: 10.1016/s0092-8674(01)00241-0. [DOI] [PubMed] [Google Scholar]
  • *35.Wang Z, Subramanya AR, Satlin LM, Pastor-Soler NM, Carattino MD, Kleyman TR. Regulation of large conductance Ca2+− activated K+ channels by WNK4 kinase. Am.J.Physiol Cell Physiol. 2013 doi: 10.1152/ajpcell.00133.2013. Study showed that WNK4 kinase system inhibits BK channels in HEK293 cells as a partial explanation for hyperkalemia in FHHt type2.
  • 36.Yue P, Zhang C, Lin DH, Sun P, Wang WH. WNK4 inhibits Ca(2+)-activated big-conductance potassium channels (BK) via mitogen-activated protein kinase-dependent pathway. Biochim.Biophys.Acta. 2013;1833:2101–2110. doi: 10.1016/j.bbamcr.2013.05.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • *37.Zhuang J, Zhang X, Wang D, Li J, Zhou B, Shi Z, Gu D, Denson DD, Eaton DC, Cai H. WNK4 kinase inhibits Maxi K channel activity by a kinase-dependent mechanism. Am.J.Physiol Renal Physiol. 2011;301:F410–F419. doi: 10.1152/ajprenal.00518.2010. Study showed that WNK4 kinase inhibited BK channels expressed in HEK cells by inhibiting its lysosomal degradation.
  • *38.Wang Z, Yue P, Lin DH, Wang WH. Carbon monoxide stimulates Ca2+ -dependent big-conductance K channels in the cortical collecting duct. Am.J.Physiol Renal Physiol. 2013;304:F543–F552. doi: 10.1152/ajprenal.00530.2012. Patch clamp study of split-open cortical collecting ducts provided evidence that local urinary CO activates BK.
  • 39.Sun P, Liu W, Lin DH, Yue P, Kemp R, Satlin LM, Wang WH. Epoxyeicosatrienoic acid activates BK channels in the cortical collecting duct. J.Am.Soc.Nephrol. 2009;20:513–523. doi: 10.1681/ASN.2008040427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Jin Y, Wang Z, Zhang Y, Yang B, Wang WH. PGE2 inhibits apical K channels in the CCD through activation of the MAPK pathway. Am.J.Physiol Renal Physiol. 2007;293:F1299–F1307. doi: 10.1152/ajprenal.00293.2007. [DOI] [PubMed] [Google Scholar]
  • 41.Liu W, Wei Y, Sun P, Wang WH, Kleyman TR, Satlin LM. Mechanoregulation of BK channel activity in the mammalian cortical collecting duct: role of protein kinases A and C. Am.J.Physiol Renal Physiol. 2009;297:F904–F915. doi: 10.1152/ajprenal.90685.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Brenner R, Perez GJ, Bonev AD, Eckman DM, Kosek JC, Wiler SW, Patterson AJ, Nelson MT, Aldrich RW. Vasoregulation by the beta1 subunit of the calcium-activated potassium channel. Nature. 2000;407:870–876. doi: 10.1038/35038011. [DOI] [PubMed] [Google Scholar]
  • 43.Pluger S, Faulhaber J, Furstenau M, Lohn M, Waldschutz R, Gollasch M, Haller H, Luft FC, Ehmke H, Pongs O. Mice with disrupted BK channel beta1 subunit gene feature abnormal Ca(2+) spark/STOC coupling and elevated blood pressure. Circ.Res. 2000;87:E53–E60. doi: 10.1161/01.res.87.11.e53. [DOI] [PubMed] [Google Scholar]
  • 44.Grimm PR, Irsik DL, Settles DC, Holtzclaw JD, Sansom SC. Hypertension of Kcnmb1−/− is linked to deficient K secretion and aldosteronism. Proc.Natl.Acad.Sci.U.S.A. 2009;106:11800–11805. doi: 10.1073/pnas.0904635106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Pluznick JL, Wei P, Carmines PK, Sansom SC. Renal fluid and electrolyte handling in BKCa-beta1−/− mice. Am.J.Physiol Renal Physiol. 2003;284:F1274–F1279. doi: 10.1152/ajprenal.00010.2003. [DOI] [PubMed] [Google Scholar]
  • 46.Nelson MT, Bonev AD. The beta1 subunit of the Ca2+-sensitive K+ channel protects against hypertension. J.Clin.Invest. 2004;113:955–957. doi: 10.1172/JCI21388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Fallet RW, Bast JP, Fujiwara K, Ishii N, Sansom SC, Carmines PK. Influence of Ca(2+)-activated K(+) channels on rat renal arteriolar responses to depolarizing agonists. Am.J.Physiol Renal Physiol. 2001;280:F583–F591. doi: 10.1152/ajprenal.2001.280.4.F583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Benchetrit S, Bernheim J, Podjarny E. Normokalemic hyperaldosteronism in patients with resistant hypertension. Isr.Med.Assoc.J. 2002;4:17–20. [PubMed] [Google Scholar]
  • 49.Gollasch M, Tank J, Luft FC, Jordan J, Maass P, Krasko C, Sharma AM, Busjahn A, Bahring S. The BK channel beta1 subunit gene is associated with human baroreflex and blood pressure regulation. J.Hypertens. 2002;20:927–933. doi: 10.1097/00004872-200205000-00028. [DOI] [PubMed] [Google Scholar]
  • 50.Senti M, Fernandez-Fernandez JM, Tomas M, Vazquez E, Elosua R, Marrugat J, Valverde MA. Protective effect of the KCNMB1 E65K genetic polymorphism against diastolic hypertension in aging women and its relevance to cardiovascular risk. Circ.Res. 2005;97:1360–1365. doi: 10.1161/01.RES.0000196557.93717.95. [DOI] [PubMed] [Google Scholar]
  • 51.Fernandez-Fernandez JM, Tomas M, Vazquez E, Orio P, Latorre R, Senti M, Marrugat J, Valverde MA. Gain-of-function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension. J.Clin.Invest. 2004;113:1032–1039. doi: 10.1172/JCI20347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Oliver WJ, Cohen EL, Neel JV. Blood pressure, sodium intake, and sodium related hormones in the Yanomamo Indians, a “no-salt” culture. Circulation. 1975;52:146–151. doi: 10.1161/01.cir.52.1.146. [DOI] [PubMed] [Google Scholar]
  • 53.Holtzclaw JD, Cornelius RJ, Hatcher LI, Sansom SC. Coupled ATP and potassium efflux from intercalated cells. Am.J.Physiol Renal Physiol. 2011;300:F1319–F1326. doi: 10.1152/ajprenal.00112.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • *54.Bugaj V, Sansom SC, Wen D, Hatcher LI, Stockand JD, Mironova E. Flow-sensitive K+-coupled ATP secretion modulates activity of the epithelial Na+ channel in the distal nephron. J.Biol.Chem. 2012;287:38552–38558. doi: 10.1074/jbc.M112.408476. Combination of clearance experiments and patch-clamp studies of native cortical collecting ducts showed that ATP coupled with BK-α/β4-mediated K secretion to inhibit ENaC-mediated Na reabsorption during high distal flow in mice.
  • 55.Stokes JB. Consequences of potassium recycling in the renal medulla. Effects of ion transport by the medullary thick ascending limb of Henle’s loop. J Clin.Invest. 1982;70:219–229. doi: 10.1172/JCI110609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Sorensen MV, Grossmann S, Roesinger M, Gresko N, Todkar AP, Barmettler G, Ziegler U, Odermatt A, Loffing-Cueni D, Loffing J. Rapid dephosphorylation of the renal sodium chloride cotransporter in response to oral potassium intake in mice. Kidney Int. 2013 doi: 10.1038/ki.2013.14. [DOI] [PubMed] [Google Scholar]
  • *57.Liu W, Schreck C, Coleman RA, Wade JB, Hernandez Y, Zavilowitz B, Warth R, Kleyman TR, Satlin LM. Role of NKCC in BK channel-mediated net K+ secretion in the CCD. Am.J.Physiol Renal Physiol. 2011;301:F1088–F1097. doi: 10.1152/ajprenal.00347.2011. Study of isolated perfused cortical collecting ducts showed that furosemide applied to basolateral membrane inhibited K secretion; evidence for functional NKCC1 in K delivery from bath to cell.

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