Recent advances in distal tubular potassium handling

Rodan, Aylin R.; Cheng, Chih Jen; Huang, Chou Long

doi:10.1152/ajprenal.00742.2010

Cited by 27 publications

(20 citation statements)

References 79 publications

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“…6,46 The KS-WNK1 level appears to be more sensitive to dietary potassium modulation. 47 In this study, we found that 10 days of HK K (10% KCl) diet feeding in mice significantly enhanced BK protein expression, which is consistent with previous findings. 34 An HK diet also reduced ERK1/2 phosphorylation, suggesting that dietary K modulates BK expression through an ERK1/2 signaling pathway.…”

Section: Hek Bka Cells Were Transfected With a Series Of Doses Of Wnksupporting

confidence: 92%

WNK1 Activates Large-Conductance Ca2+-Activated K+ Channels through Modulation of ERK1/2 Signaling

Liu

Song

Shi

et al. 2015

Journal of the American Society of Nephrology

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With no lysine (WNK) kinases are members of the serine/threonine kinase family. We previously showed that WNK4 inhibits renal large-conductance Ca 2+ -activated K + (BK) channel activity by enhancing its degradation through a lysosomal pathway. In this study, we investigated the effect of WNK1 on BK channel activity. In HEK293 cells stably expressing the a subunit of BK (HEK-BKa cells), siRNA-mediated knockdown of WNK1 expression significantly inhibited both BKa channel activity and open probability. Knockdown of WNK1 expression also significantly inhibited BKa protein expression and increased ERK1/2 phosphorylation, whereas overexpression of WNK1 significantly enhanced BKa expression and decreased ERK1/2 phosphorylation in a dose-dependent manner in HEK293 cells. Knockdown of ERK1/2 prevented WNK1 siRNA-mediated inhibition of BKa expression. Similarly, pretreatment of HEK-BKa cells with the lysosomal inhibitor bafilomycin A1 reversed the inhibitory effects of WNK1 siRNA on BKa expression in a dose-dependent manner. Knockdown of WNK1 expression also increased the ubiquitination of BKa channels. Notably, mice fed a high-K + diet for 10 days had significantly higher renal protein expression levels of BKa and WNK1 and lower levels of ERK1/2 phosphorylation compared with mice fed a normal-K + diet. These data suggest that WNK1 enhances BK channel function by reducing ERK1/2 signaling-mediated lysosomal degradation of the channel. With no lysine (WNK) kinase belongs to a family of serine/threonine kinases. Mutations of WNK1 and WNK4 are responsible for pseudohypoaldosteronism type II (PHAІІ), characterized by hypertension, hyperkalemia, and metabolic acidosis. 1,2 The disease mutation in WNK1 or WNK4 kinase resulting in hyperkalemia suggests a role of WNK in potassium handling in renal distal nephron, which contains two major potassium channels, renal outer medullary K + channels (ROMK) and Big K (BK) channels. 3,4 WNK4 inhibits ROMK channel activity and its surface expression, whereas WNK4 disease mutant enhances its inhibitory effect on ROMK. 5 WNK1 also inhibits ROMK activity; however, a kidney-specific form of WNK1 (KS-WNK1) reverses WNK1's effect on ROMK. 6 WNK4 inhibits BK channel activity and protein expression, 7-9 whereas WNK4 disease mutant also enhances its inhibitory effect on BK activity via a ubiquitin-dependent pathway. 9 BK channel (or Maxi K) is a large conductance Ca 2+ and voltage-activated K channel. 10 BK is encoded by the gene slo1 11 and is widely distributed in many different

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Section: Hek Bka Cells Were Transfected With a Series Of Doses Of Wnksupporting

confidence: 92%

WNK1 Activates Large-Conductance Ca2+-Activated K+ Channels through Modulation of ERK1/2 Signaling

Liu

Song

Shi

et al. 2015

Journal of the American Society of Nephrology

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“…In many excitable cell types, such as neurons and muscle cells, only slight Na + permeability is observed in the resting state, and it increases when an action potential is produced [4,11,15,28]. Some nonexcitable cell types, including renal epithelial cells, exhibit significant Na + permeability, but it is less than other ion permeabilities [30]. Accordingly, fibrocyte membrane profile appears to be relatively unique, although it may occur in other cell types that have not yet been characterized by electrophysiological experiments.…”

Section: Discussionmentioning

confidence: 99%

“…The negative RMP induced by K + permeability is also seen in non-excitable cells, including astroglia and retinal Müller cells [8]. Other cell types, such as epithelial cells and cardiac fibroblasts, show a less polarized RMP, but the potential never exceeds 0 mV [20,30]. In contrast, the mammalian cochlea contains an atypical cell type that deviates from this fundamental property of having a negative RMP.…”

Section: Introductionmentioning

confidence: 99%

The unique ion permeability profile of cochlear fibrocytes and its contribution to establishing their positive resting membrane potential

Yoshida

Nin

Murakami

et al. 2016

Pflugers Arch - Eur J Physiol

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Eukaryotic cells exhibit negative resting membrane potential (RMP) owing to the high K(+) permeability of the plasma membrane and the asymmetric [K(+)] between the extracellular and intracellular compartments. However, cochlear fibrocytes, which comprise the basolateral surface of a multilayer epithelial-like tissue, exhibit a RMP of +5 to +12 mV in vivo. This positive RMP is critical for the formation of an endocochlear potential (EP) of +80 mV in a K(+)-rich extracellular fluid, endolymph. The epithelial-like tissue bathes fibrocytes in a regular extracellular fluid, perilymph, and apically faces the endolymph. The EP, which is essential for hearing, represents the potential difference across the tissue. Using in vivo electrophysiological approaches, we describe a potential mechanism underlying the unusual RMP of guinea pig fibrocytes. The RMP was +9.0 ± 3.7 mV when fibrocytes were exposed to an artificial control perilymph (n = 28 cochleae). Perilymphatic perfusion of a solution containing low [Na(+)] (1 mM) markedly hyperpolarized the RMP to -31.1 ± 11.2 mV (n = 10; p < 0.0001 versus the control, Tukey-Kramer test after one-way ANOVA). Accordingly, the EP decreased. Little change in RMP was observed when the cells were treated with a high [K(+)] of 30 mM (+10.4 ± 2.3 mV; n = 7; p = 0.942 versus the control). During the infusion of a low [Cl(-)] solution (2.4 mM), the RMP moderately hyperpolarized to -0.9 ± 3.4 mV (n = 5; p < 0.01 versus the control), although the membranes, if governed by Cl(-) permeability, should be depolarized. These observations imply that the fibrocyte membranes are more permeable to Na(+) than K(+) and Cl(-), and this unique profile and [Na(+)] gradient across the membranes contribute to the positive RMP.

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“…In the setting of high-K ϩ intake, particularly in experimental animals where a 5 to 10 time higher K ϩ load is given, Na ϩ -dependent K ϩ secretion would amount to ϳ50% of Na ϩ reabsorption via ENaC. A mechanism for Na ϩ -independent K ϩ secretion, such as via parallel K ϩ and Cl Ϫ secretion (19), would allow animals to uncouple K ϩ secretion from Na ϩ reabsorption and volume homeostasis. On the surface, our finding that amiloride completely inhibits K ϩ secretion in CCD from high K ϩ -treated mice seems to contradict to the notion of ENaC-independent K ϩ secretion.…”

Section: Discussionmentioning

confidence: 99%

Kidney-specific WNK1 regulates sodium reabsorption and potassium secretion in mouse cortical collecting duct

Cheng

Baum

Huang

2013

American Journal of Physiology-Renal Physiology

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Kidney-specific with-no-lysine kinase 1 (KS-WNK1) is a kinase-deficient variant of WNK1 that is expressed exclusively in the kidney. It is abundantly expressed in the distal convoluted tubule (DCT) and to a lesser extent in the cortical thick ascending limb (cTAL), connecting tubule, and cortical collecting duct (CCD). KS-WNK1 inhibits Na(+)-K(+)-2Cl(-)- and sodium chloride cotransporter-mediated Na(+) reabsorption in cTAL and DCT, respectively. Here, we investigated the role of KS-WNK1 in regulating Na(+) and K(+) transport in CCD using in vitro microperfusion of tubules isolated from KS-WNK1 knockout mice and control wild-type littermates. Because baseline K(+) secretion and Na(+) reabsorption were negligible in mouse CCD, we studied tubules isolated from mice fed a high-K(+) diet for 2 wk. Compared with that in wild-type tubules, K(+) secretion was reduced in KS-WNK1 knockout CCD perfused at a low luminal fluid rate of ~1.5 nl/min. Na(+) reabsorption and the lumen-negative transepithelial potential difference were also lower in the KS-WNK1 knockout CCD compared with control CCD. Increasing the perfusion rate to ~5.5 nl/min stimulated K(+) secretion in the wild-type as well as knockout CCD. The magnitudes of flow-stimulated increase in K(+) secretion were similar in wild-type and knockout CCD. Maxi-K(+) channel inhibitor iberiotoxin had no effect on K(+) secretion when tubules were perfused at ~1.5 nl/min, but completely abrogated the flow-dependent increase in K(+) secretion at ~5.5 nl/min. These findings support the notion that KS-WNK1 stimulates ROMK-mediated K(+) secretion, but not flow-dependent K(+) secretion mediated by maxi-K(+) channels in CCD. In addition, KS-WNK1 plays a role in regulating Na(+) transport in the CCD.

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Recent advances in distal tubular potassium handling

Cited by 27 publications

References 79 publications

WNK1 Activates Large-Conductance Ca2+-Activated K+ Channels through Modulation of ERK1/2 Signaling

WNK1 Activates Large-Conductance Ca2+-Activated K+ Channels through Modulation of ERK1/2 Signaling

The unique ion permeability profile of cochlear fibrocytes and its contribution to establishing their positive resting membrane potential

Kidney-specific WNK1 regulates sodium reabsorption and potassium secretion in mouse cortical collecting duct

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