|Year : 2017 | Volume
| Issue : 3 | Page : 75-80
Sodium-chloride cotransporter activity regulated by extracellular potassium
Siqi Ying, Yang Yang, Chong Zhang
Department of Nephrology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
|Date of Web Publication||28-Sep-2017|
Department of Nephrology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Shi
Source of Support: None, Conflict of Interest: None
The thiazide-sensitive sodium-chloride cotransporter (NCC) is exclusively expressed in the apical membrane of the renal distal convoluted tubule (DCT), and it is important for maintaining fluid and salt balance. NCC is responsible for electroneutral NaCl reabsorption, and its activity is determined by phosphorylation, which was reported to be regulated by WNK-stimulated Ste20-type kinases, Ste20-related proline alanine-rich kinase, and oxidative stress response 1 kinase. WNK kinases have chloride-binding sites, and WNK4 has the highest sensitivity to intracellular chloride concentration ([Cl−]i) compared with WNK1 and WNK3. NCC dysfunction often comes together with abnormal urinary potassium excretion, which is not only highlighted by Mendelian disorders such as familial hyperkalemic hypertension (FHHt) and Gitelman syndrome but also presented more frequently by long-term usage of thiazides, specific inhibitors of NCC. Recent studies have shown that extracellular potassium (K+) can modulate DCT cell membrane voltage and in turn intracellular Cl−, which regulates phosphorylation of WNK kinases. Additional Cl− independent mechanisms were also reported by several groups. This paper is a brief review of the recent discoveries on mechanisms of NCC regulation by extracellular potassium.
Keywords: Chloride, extracellular potassium, sodium-chloride cotransporter, WNK kinases
|How to cite this article:|
Ying S, Yang Y, Zhang C. Sodium-chloride cotransporter activity regulated by extracellular potassium. J Integr Nephrol Androl 2017;4:75-80
| Introduction|| |
The distal convoluted tubule (DCT) plays a pivotal role in maintaining fluid and salt balance, which reabsorbs 5%–10% of the salt filtered by the glomerulus every day. The DCT is divided into two functionally distinct segments: the proximal portion of the DCT (DCT1) and the remote one (DCT2). Sodium-chloride cotransporter (NCC), which is crucial for blood pressure regulation and electrolyte balance, is primarily located in the DCT1 and reabsorbs Na + and Cl − in an electroneutral manner while electrogenic sodium channel, the epithelial sodium channel (ENaC), is expressed from DCT2 to latter parts of distal tubule. The renal outer medullary potassium channel (ROMK) is expressed along the entire distal nephron from the thick ascending limb through the collecting ducts (CDs). NCC is not directly involved in the transportation or excretion of K +; however, it is interesting that NCC dysregulation is almost always accompanied by hyperkalemia or hypokalemia. Abnormal NCC activities result from genetic disorders such as Gitelman syndrome, EAST/SeSAME syndrome, and familial hyperkalemic hypertension (FHHt) (also known as Gordon syndrome or pseudohypoaldosteronism type II), present excessive or diminished urinary potassium excretion, respectively. Gitelman syndrome is due to inactivating mutations in SLC12A3 which encodes NCC, featuring hypotension, hypokalemia, metabolic alkalosis, and hypocalcemia. Loss-of-function mutations of Kcnj10 cause EAST/SeSAME syndrome in humans which is also relevant to decreased NCC function (see below for details). The patients of EAST/SeSAME syndrome usually suffer from epilepsy, ataxia, sensorineural deafness, and other complex neurological symptoms in addition to hypokalemia and metabolic alkalosis caused by the renal tubule damage similar to Gitelman syndrome., In contrast, overactivation of the NCC in FHHt results in hypertension, hyperkalemia, metabolic acidosis, and hypercalcemia. Therefore, one can hypothesize that activation of NCC can lead to potassium retention; NCC inactivation is to promote potassium excretion. NCC is not only supposed to regulate the excretion of K + but also its activity is regulated by serum or extracellular K +, which is reflected in the scenarios of NCC rapid dephosphorylation after high potassium diet (HK) and NCC phosphorylation after the low potassium diet (LK). It appears that NCC serves as an extracellular K + sensor. When the extracellular K + concentration ([K +]ex) is high, NCC is suppressed. Contrarily, when the [K +]ex is low, the opposite occurs. The activity of NCC is proposed to be the determinant of downstream tubule K + excretion. When NCC is inhibited, more Na + is transported to aldosterone-sensitive distal nephron (comprising the connecting tubule and CD and in some species, the DCT2), which facilitate electrogenic absorption by ENaC and K + excretion by the coupled ROMK. This review aims to summarize the latest advances in the regulation of NCC activity by extracellular K +.
| WNK-Ste20-Related Proline Alanine-Rich Kinase/oxidative Stress Response 1 Kinase-Sodium-Chloride Cotransporter Phosphorylation Cascade|| |
NCC is regulated by phosphorylation at conserved threonine and serine residues in the amino-terminal domain., Ste20-related proline alanine-rich kinase (SPAK) and oxidative stress response 1 kinase (OSR1) which are phosphorylated by WNK kinases can phosphorylate NCC directly.,
The WNK kinases are a family of four evolutionarily conserved serine-threonine kinases, WNK1 to WNK4, which was nominated for its lack of lysine in the second subunit of the kinase domain that is crucial for binding ATP. WNK1, WNK3, and WNK4, but not WNK2, are expressed in the kidney. Up to date, four mutated genes have been implicated in FHHt: two coding for kinases (WNK1 and WNK4) and the other two coding for ubiquitinylases (the cullin RING ligases family members kelch-like 3 [KLHL3] and cullin3 [CUL3]). These four proteins are involved in the network of NCC activity-regulated signaling pathways. WNK1 and WNK4 regulate NCC activity through SPAK/OSR1 phosphorylation, and KLHL3 and CUL3 modulate the degradation of WNK kinase through a ubiquitylation mechanism.,
There are many different WNK1 isoforms expressed in mammals. Full-length WNK1 (also called long-WNK1, L-WNK1) contains the entire kinase domain, widely expressed in a variety of human tissues, while a shorter, kidney-specific WNK1 (KS-WNK1) is only expressed in the distal nephron and is devoid of kinase activity. In the initial study of Xenopus laevis oocytes, L-WNK1 was reported to antagonize the inhibitory effect of WNK4 on NCC instead of a direct NCC activation. However, L-WNK1 phosphorylates SPAK, indicating that L-WNK1 can phosphorylate NCC through a SPAK-dependent mechanism., Recent studies have shown that WNK1 has several alternatively splicing isoforms of exons 9, 11, 12, and 26. The predominant isoform in the kidney is WNK1-Δ11 (only lacking exon 11), which was proved to be a potent activator of NCC in Xenopus oocytes. Moreover, WNK1-FHHt mice (deletions in intron 1 of the WNK1 gene) fully showed FHHt phenotype with increased L-WNK1 expression and no change in KS-WNK1 expression. The mice also appeared increased phosphorylation levels of SPAK and NCC on DCT. All above indicate that L-WNK1 activates NCC.
Like L-WNK1, WNK3 also activates NCC in vitro through a SPAK-dependent pathway., In contrast, the phosphorylation and expression levels of OSR1, SPAK, NKCC2, and NCC in the kidneys of WNK3 knockout mice were not reduced in either normal or low-salt diets, suggesting that WNK3's effect on NCC is minimal in vivo.
Whether the effect of WNK4 on NCC is positive or negative had been debated for a long time. Studies employing heterologous expression of WNK4 in Xenopus oocytes , and mammalian cell systems , typically reported that WNK4 inhibited NCC. The experiment of mDCT15 cell line showed that reducing endogenous WNK4 using a small hairpin RNA was followed by an increase in NCC activity and membrane expression. On the contrary, almost all in vivo data support that WNK4 activates NCC. The phosphorylation levels of SPAK and NCC were significantly reduced in WNK4 knockout (WNK4- KO) mice, showing a Gitelman-like phenotype including hypokalemia and metabolic alkalosis. Although there was a marked increase in WNK1 expression, it could not compensate for WNK4 deficiency in the DCT, indicating that WNK4 is the major positive regulator of NCC in the kidney. It was further supported by unique chloride-sensing properties of WNK4 (see below for details). Animal models of FHHt disease mutant of WNK4 D561A knockin,, transgenic mice carrying multiple copies of wild-type WNK4 gene, and mice carrying KLHL3 mutations  were demonstrated to exhibit FHHt phenotype, showing without exception the increased abundance of WNK4 and phosphorylation of SPAK/OSR1 and NCC. Taken together, all these mouse models support that WNK4 has a positive effect on NCC.
| Chloride-Sensing Properties of WNK Kinases|| |
WNK kinases are reported to be chloride-sensitive. Recent studies have shown that the intracellular chloride concentration [Cl −]i inhibits autophosphorylation and activity of WNK1 and WNK4, thereby preventing NCC phosphorylation. Piala et al. reported that two key leucine residues, Leu369 and Leu371 in the L-WNK1 kinase domain, can bind to Cl −, thereby abolishing the autophosphorylation and activation of the kinase. Similarly, the effect of WNK4 on NCC is also regulated by [Cl −]i. Mutating Leu322 in WNK4 impeded the binding between WNK4 and Cl −, resulting in the constitutive phosphorylation and activation of WNK4. WNK4 is inhibited at high [Cl −]i. Conversely, WNK4 can be phosphorylated at low [Cl −]i. Furthermore, WNKs have different chloride affinity. Compared with WNK1 and WNK3, WNK4 is the most sensitive to [Cl −]i. The affinity profile is probably WNK4 >WNK1 >WNK3.
| Sodium-Chloride Cotransporter Regulation by Extracellular K +|| |
Nowadays, individuals consuming a Western diet typically ingest approximately 50–100 mEq (2–4 g) potassium daily,, which is much less than our ancestors thousands of years ago. In the body, most of K + is located inside the cell while extracellular fluid contains only 50–80 mEq K +. Thus, even a single meal might contain more K + than that is present in the extracellular fluid, presenting a substantial physiologic challenge. A HK meal might raise plasma K +, and plasma K + is buffered by both renal and extrarenal mechanisms. Approximately 90% of the daily intake of K + is excreted from the kidneys by urine and <10% is excreted by the gastrointestinal tract. Plasma K + also can be reduced by transferring K + into the cells. Thus, large and potential harmful swings in plasma K + typically do not occur during the day, and kidneys play a dominant role in K + balance. Several studies demonstrated that NCC phosphorylation is modulated by dietary potassium intake. HK diet suppresses , and LK intake increases , NCC activity.
Recently, an elegant experiment performed by Terker et al. convincingly proved that the activity of the WNK-SPAK signaling pathway in the DCT is regulated by extracellular K + such that hyperkalemia inhibits, whereas hypokalemia stimulates NCC phosphorylation. A possible hypothesis for the explanation of such effects comes from recent observations in a mouse model of EAST/SeSAME syndrome. EAST/SeSAME syndrome is an autosomal recessive disease, caused by loss-of-function mutations in the KCNJ10 gene. The KCNJ10 gene encodes an inwardly rectifying potassium channel 4.1 (Kir4.1) that is expressed in certain neurons and in the basolateral plasma membrane of the DCT. Kir4.1 activity is essential for maintaining cell membrane potential. Intracellular K + leaves the cell through activated Kir4.1, which promotes DCT cell hyperpolarization with a consequent chloride efflux, thus decreasing [Cl −]i activating NCC through a WNK4-SPAK-dependent mechanism.KCNJ10 knockout mice showed that impaired Kir4.1 activity resulted in depolarizing basolateral membrane of DCT cells and reducing the electrochemical driving force of ClC-K Cl − channels, which raised [Cl −]i and then inhibited WNK-SPAK-NCC cascade., Therefore, the activity of Kir4.1 plays a key role in the regulation of NCC activity, and the increase in [Cl −]i induced by membrane depolarization is responsible for the inhibition of NCC activity in DCT cells expressing loss-of-function mutants of KCNJ10. Terker et al. reported extracellular K + modulates Kir4.1 directly, by which hyperkalemia depolarizes membrane potential, finally leading to NCC inactivation, and vice versa. Furthermore, the modest change of plasma K + within the physiological range, which is often seen in daily life, is enough to induce different levels of NCC phosphorylation.
Apart from regulating the WNK-SPAK-NCC cascade by a Cl − dependent pathway, evidence emerged from several different groups suggesting extracellular K + can also modulate NCC phosphorylation through additional signaling pathway which is likely to be Cl − independent. For example, SPAK/OSR1 single- and double-knockout mice were still able to modulate NCC phosphorylation to some extent in response to LK intake,, indicating another regulation pathway of NCC in which WNK-SPAK/OSR1 are not involved. NCC dephosphorylation triggered by HK is neither blocked by removing extracellular Cl − nor by the Cl − channel blocker 4,4'-diisothiocyano-2,2'-stilbenedisulphonic acid. Ishizawa et al. demonstrated that the KLHL3/CUL3-based ubiquitin ligase is involved in the LK-mediated activation of NCC. Shoda et al. proposed that HK diet can activate calcineurin, which dephosphorylates NCC quickly, promoting urinary potassium excretion.
| The Effect of Aldosterone|| |
Aldosterone is regarded as a principal hormone handling renal K + excretion while it also regulates Na + balance and blood pressure. When HK diet increases plasma K +, aldosterone is secreted by adrenal zona glomerulosa to promote renal excretion of potassium. Aldosterone binds to mineralocorticoid receptor (MR) and then activates ENaC. The inwardly rectifying K + channel ROMK excretes K + with the help of the negative potential of lumen generated by ENaC. Several groups reported that mice treated with direct infusion of aldosterone  or dietary salt restriction , displayed an increase of plasma aldosterone and NCC activation, so the authors concluded that aldosterone can activate NCC. However, a recent study showed deficient NCC activity in renal MR knockout mice and NCC could be activated by restricting dietary K +, suggesting that aldosterone's effect on NCC is secondary to the changes in plasma K +, rather than direct activation. Moreover, NCC phosphorylation was no more incurred in wide-type mice fed with HK diet to correct the hypokalemia caused by aldosterone injection. Todkar et al. found NCC phosphorylation could still be inhibited in aldosterone synthase gene knockout (AS −/−) on HK diet although the abundance of ENaC and ROMK was higher in AS −/− than AS +/+. In addition, the nephron-specific α-subunit of ENaC knockout mice fed a regular-salt diet exhibited downregulated expression and phosphorylation of NCC, despite high plasma aldosterone levels., It is worth noting that urinary K + excretion induced by HK diet is often present before serum aldosterone is elevated, suggesting alternative aldosterone-independent pathway such as Maxi-K (BK) for K + excretion.
| Summary|| |
NCC can be directly regulated by extracellular K +, and it serves as an extracellular K + sensor to switch on or off downstream K + excretion. Extracellular K + changes the cell membrane potential in distal tubule through Kir4.1, affecting [Cl −]i. When [K +]ex is high, [Cl −]i is increased and vice versa. WNKs are chloride-sensing kinases, when binding to Cl −, the dephosphorylation of WNK4 inhibits downstream phosphorylation of SPAK/OSR1 and NCC. In addition, extracellular K + can also modulate NCC phosphorylation through a WNK-SPAK/OSR1 and chloride-independent manner which remains to be clarified.
| Prospective|| |
Compared to diets consumed by our evolutionary ancestors, most people in the world today consume a diet relatively high in salt and low in K +. The distal tubule of the mammalian kidney is designed to facilitate K + excretion which is accommodated to HK diet of ancient times. Unrestricted activation of NCC caused by typical modern LK diet is likely account for the rapid rise in hypertension prevalence, which is a major public health issue. HK diet intake is proved to result in lowered blood pressure and decreased mortality in the population. Figuring out the mechanism of NCC regulation by extracellular K + holds considerable promise for the development of novel antihypertensive drugs and diuretics.
Financial support and sponsorship
This work was supported by the National Natural Science Foundation of China 81570634 and 81770706.
Conflicts of interest
There are no conflicts of interest.
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