Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension

Ronzaud, Caroline; Loffing‐Cueni, Dominique; Hausel, Pierrette; Debonneville, Anne; Malsure, Sumedha; Fowler-Jaeger, Nicole; Boase, Natasha A.; Perrier, Romain; Maillard, Marc; Yang, Baoli; Stokes, John B.; Koesters, Robert; Kumar, Sharad; Hummler, Edith; Loffing, Johannes; Staub, Olivier

doi:10.1172/jci61110

Cited by 103 publications

(176 citation statements)

References 56 publications

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“…The increased Na + reabsorption by NCC would decrease Na + delivery to ENaC, thus impairing the electrochemical gradient required for K + secretion by ROMK and H + by the vacuolar H + -ATPase. Other mouse models with increased NCC activity do not, however, display hyperkalemia or metabolic acidosis (18,26,27). In addition, we found that ENaC activity is conserved in WNK1 +/FHHt animals.…”

Section: Discussionmentioning

confidence: 59%

WNK1 -related Familial Hyperkalemic Hypertension results from an increased expression of L-WNK1 specifically in the distal nephron

Vidal‐Petiot

Elvira-Matelot

Mutig

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

118

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Large deletions in the first intron of the With No lysine (K) 1 (WNK1) gene are responsible for Familial Hyperkalemic Hypertension (FHHt), a rare form of human hypertension associated with hyperkalemia and hyperchloremic metabolic acidosis. We generated a mouse model of WNK1-associated FHHt to explore the consequences of this intronic deletion. WNK1 +/FHHt mice display all clinical and biological signs of FHHt. This phenotype results from increased expression of long WNK1 (L-WNK1), the ubiquitous kinase isoform of WNK1, in the distal convoluted tubule, which in turn, stimulates the activity of the Na-Cl cotransporter. We also show that the activity of the epithelial sodium channel is not altered in FHHt mice, suggesting that other mechanisms are responsible for the hyperkalemia and acidosis in this model. Finally, we observe a decreased expression of the renal outer medullary potassium channel in the late distal convoluted tubule of WNK1 +/FHHt mice, which could contribute to the hyperkalemia. In summary, our study provides insights into the in vivo mechanisms underlying the pathogenesis of WNK1-mediated FHHt and further corroborates the importance of WNK1 in ion homeostasis and blood pressure. The human mutations identified at the WNK1 locus do not modify the coding sequence but are large deletions in the 60-kb-long first intron, which result in an overexpression of WNK1 in the leukocytes of patients (3). The WNK1 gene generates two isoforms through alternative promoters. The long isoform, long WNK1 (L-WNK1), is expressed ubiquitously, whereas the shorter isoform, kidney-specific WNK1 (KS-WNK1), which lacks a functional kinase domain, is expressed specifically in the kidney (5). In the kidney, L-WNK1 is expressed at a low level in all nephron segments, whereas KS-WNK1 is expressed only in the distal nephron (6). We previously generated a transgenic mouse model that exhibited an ectopic expression of KS-WNK1 and an increased expression of L-WNK1 in the distal nephron on deletion of the first intron (7). This model, however, did not allow the study of the functional consequences of the deletion of WNK1 first intron, because a reporter gene was inserted under the control of each WNK1 promoter within the transgene.Several in vitro experiments suggest that an increase in L-WNK1 expression in the distal nephron could trigger the development of FHHt. The kinase can, indeed, stimulate the activity of the Na + -Cl − cotransporter (NCC), which has been established as an essential component of the FHHt phenotype, through its interaction with either WNK4 and/or Ste20-related proline-alanine rich kinase (SPAK) (review in ref. 4). WNK4 inhibits NCC, and L-WNK1 relieves the cotransporter from this inhibition. L-WNK1 phosphorylates and thus, activates SPAK, which in turn, stimulates NCC membrane expression by phosphorylation. However, the characterization of L-WNK1 function in the distal nephron has been hampered by the absence of a valid mouse model, because L-WNK1 inactivation results in embryonic death caused by cardiovasc...

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Section: Discussionmentioning

confidence: 59%

WNK1 -related Familial Hyperkalemic Hypertension results from an increased expression of L-WNK1 specifically in the distal nephron

Vidal‐Petiot

Elvira-Matelot

Mutig

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

118

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“…Recent data indicate that Nedd4-2 is yet another player in the pathway by which aldosterone activates NCC (Figure 3) [2,99]. Nedd4-2 was shown to stimulate ubiquitylation of NCC and decreased its activity and surface expression in vitro and in vivo, while SGK1 prevented these effects [2].…”

Section: Ubiquitin Ligasesmentioning

confidence: 99%

“…This NCC signaling cascade consists of a multikinase network which includes the kinases WNK, SPAK, OSR1, and SGK1 [130]. More recently, proteins involved in ubiquitylation including Nedd4-2, Kelch-like 3, and Cullin 3 were also found to regulate NCC [2,7,68,99]. Many of these regulatory proteins were identified because mutations in their genes result in familial hyperkalemic hypertension (FHHt, also called pseudohypoaldosteronism type II or Gordon syndrome, see also "Relation to diseases" below).…”

Section: Kinasesmentioning

confidence: 99%

“…Nedd4-2 was shown to stimulate ubiquitylation of NCC and decreased its activity and surface expression in vitro and in vivo, while SGK1 prevented these effects [2]. The pathophysiological significance of the regulation of NCC by Nedd4-2 was shown by the generation of inducible nephron-specific Nedd4-2 knockout mice [99]. These mice exhibited salt-dependent hypertension that was characterized by upregulation of total and phosphorylated NCC and sensitivity to thiazides.…”

Section: Ubiquitin Ligasesmentioning

confidence: 99%

“…Although this review focused on NCC, sodium excretion by the kidney depends on many other sodium transporters, including NHE3, NKCC2, ENaC, and pendrin. Stimuli that activate NCC, sometimes also activate these other transporters, but an opposite, compensatory response may also occur [38,84,99]. In conclusion, the role of NCC in normal physiology and in the pathophysiology of hypertension is expanding and will 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 20 likely continue to do so in coming years.…”

Section: Perspectivesmentioning

confidence: 99%

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The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

Moes

Lubbe

Zietse

et al. 2013

Pflugers Arch - Eur J Physiol

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SLC12A3 encodes the thiazide-sensitive sodium chloride cotransporter (NCC), which is primarily expressed in the kidney, but also in intestine and bone. In the kidney, NCC is located in the apical plasma membrane of epithelial cells in the distal convoluted tubule. Although NCC reabsorbs only 5 to 10 % of filtered sodium, it is important for the fine-tuning of renal sodium excretion in response to various hormonal and non-hormonal stimuli. Several new roles for NCC in the regulation of sodium, potassium, and blood pressure have been unraveled recently. For example, the recent discoveries that NCC is activated by angiotensin II but inhibited by dietary potassium shed light on how the kidney handles sodium during hypovolemia (high angiotensin II) and hyperkalemia. The additive effect of angiotensin II and aldosterone maximizes sodium reabsorption during hypovolemia, whereas the inhibitory effect of potassium on NCC increases delivery of sodium to the potassium-secreting portion of the nephron. In addition, great steps have been made in unraveling the molecular machinery that controls NCC. This complex network consists of kinases and ubiquitinases, including WNKs, SGK1, SPAK, Nedd4-2, Cullin-3, and Kelch-like 3. The pathophysiological significance of this network is illustrated by the fact that modification of each individual protein in the network changes NCC activity and results in salt-dependent hypotension or hypertension. This review aims to summarize these new insights in an integrated manner while identifying unanswered questions.

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Distal Convoluted Tubule

McCormick

Ellison

2014

Comprehensive Physiology

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The distal convoluted tubule (DCT) is a short nephron segment, interposed between the macula densa and collecting duct. Even though it is short, it plays a key role in regulating extracellular fluid volume and electrolyte homeostasis. DCT cells are rich in mitochondria, and possess the highest density of Na + /K + -ATPase along the nephron, where it is expressed on the highly amplified basolateral membranes. DCT cells are largely water impermeable, and reabsorb sodium and chloride across the apical membrane via electroneurtral pathways. Prominent among this is the thiazide-sensitive sodium chloride cotransporter, target of widely used diuretic drugs. These cells also play a key role in magnesium reabsorption, which occurs predominantly, via a transient receptor potential channel (TRPM6). Human genetic diseases in which DCT function is perturbed have provided critical insights into the physiological role of the DCT, and how transport is regulated. These include Familial Hyperkalemic Hypertension, the salt-wasting diseases Gitelman syndrome and EAST syndrome, and hereditary hypomagnesemias. The DCT is also established as an important target for the hormones angiotensin II and aldosterone; it also appears to respond to sympathetic-nerve stimulation and changes in plasma potassium. Here, we discuss what is currently known about DCT physiology. Early studies that determined transport rates of ions by the DCT are described, as are the channels and transporters expressed along the DCT with the advent of molecular cloning. Regulation of expression and activity of these channels and transporters is also described; particular emphasis is placed on the contribution of genetic forms of DCT dysregulation to our understanding.

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Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension

Cited by 103 publications

References 56 publications

WNK1 -related Familial Hyperkalemic Hypertension results from an increased expression of L-WNK1 specifically in the distal nephron

WNK1 -related Familial Hyperkalemic Hypertension results from an increased expression of L-WNK1 specifically in the distal nephron

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

Distal Convoluted Tubule

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