The Syndrome of Hypertension and Hyperkalaemia without Renal Failure: Long Term Correction by Thiazide Diuretic

Gordon, Richard D.; Hodsman, G P

doi:10.1177/003693308603100114

Cited by 58 publications

(40 citation statements)

References 2 publications

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“…A third potential site is the thiazide-sensitive Na-Cl cotransporter in distal convoluted tubule. The familial syndrome of low-renin hyperkalemic hypertension known as pseudohypoaldosteronism type II (PHA II) 38,39 is qualitatively similar to what we observe in blacks. It has been shown to result from mutations in serine/threonine kinases that presumably enhance the activity of the cotransporter.…”

Section: Discussionsupporting

confidence: 73%

Racial Difference in the Activity of the Amiloride-Sensitive Epithelial Sodium Channel

et al. 2002

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Abstract-Compared with whites, blacks appear to retain additional sodium that suppresses secretion of renin and aldosterone. The epithelial sodium channel (ENaC) is an aldosterone-regulated site for sodium reabsorption. ENaC activity could be higher in blacks, contributing to sodium retention or, alternatively, lower because of reduced stimulation by aldosterone. To examine the level of ENaC activity in blacks relative to whites, blood pressure (BP) responses to amiloride (5 mg/d), an inhibitor of ENaC, were measured in 20 black and 25 white normotensive young people. After 1 week, systolic BP decreased by 3.0Ϯ9.2 (SD) and diastolic by 2.8Ϯ8.3 mm Hg in the whites, whereas systolic BP increased by 2.5Ϯ7.1 and diastolic by 3.8Ϯ8.0 mm Hg in the blacks; the racial difference in the BP response was significant for both systolic (Pϭ0.034) and diastolic BP (Pϭ0.010). As ENaC activity increases, renal secretion of potassium increases proportionately, and in a larger sample of subjects, the urinary potassium excretion rate was lower in the blacks (nϭ301) than in the whites (nϭ461): 3.2Ϯ0.1 versus 3.8Ϯ0.1 mmol/mmol creatinine (Pϭ0.0001). The concentration of serum potassium was higher in the blacks (nϭ81) than in the whites (nϭ167)

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Section: Discussionsupporting

confidence: 73%

Racial Difference in the Activity of the Amiloride-Sensitive Epithelial Sodium Channel

et al. 2002

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“…Its deletion in WNK1 +/FHHt mice and FHHt patients could, therefore, cause the activation of L-WNK1 promoter by the renal enhancer, resulting in an increased expression of L-WNK1 in the DCT and CNT without affecting KS-WNK1 expression. The complete correction of the phenotype by thiazide diuretics in both patients and mouse models (1,24,25), including our model, suggests that increased NCC activity is sufficient to generate hyperkalemia and metabolic acidosis. 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.…”

Section: Discussionmentioning

confidence: 66%

“…sodium transport | transgenic mouse | potassium balance F amilial Hyperkalemic Hypertension (FHHt) is a rare disorder featuring hypertension, hyperkalemia, and hyperchloremic metabolic acidosis (Online Mendelian Inheritance in Man, OMIM, 145260) (1,2). Twelve years ago, mutations in the With No lysine (K) 1 (WNK1) and WNK4 genes were shown to cause FHHt (3), initiating a field of extensive research on the regulation of blood pressure and ion homeostasis by these two serine-threonine kinases of the WNK family (review in ref.…”

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confidence: 99%

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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“…The degree of hyperkalemia can be dramatic, with levels of Ͼ8 mmol/L reported in untreated individuals. 15,16 Its origin was puzzling, although increased NCCT activity in the distal convoluted tubule would be expected to reduce NaCl entering the collecting duct, hence reducing electrogenic Na ϩ uptake and subsequent K ϩ secretion through ROMK. Based on the 6-to 7-fold shift in sensitivity to thiazides reported in subjects with Gordon's, in vivo activation of NCCT appears to be substantial.…”

Section: Golbang Et Almentioning

confidence: 99%

A New Kindred With Pseudohypoaldosteronism Type II and a Novel Mutation (564D>H) in the Acidic Motif of the WNK4 Gene

et al. 2005

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Abstract-We identified a new kindred with the familial syndrome of hypertension and hyperkalemia (pseudohypoaldosteronism type II or Gordon's syndrome) containing an affected father and son. Mutation analysis confirmed a single heterozygous G to C substitution within exon 7 (1690GϾC) that causes a missense mutation within the acidic motif of WNK4 (564DϾH). We confirmed the function of this novel mutation by coexpressing it in Xenopus oocytes with either the NaCl cotransporter (NCCT) or the inwardly rectifying K-channel (ROMK). Wild-type WNK4 inhibits 22 Na ϩ flux in Xenopus oocytes expressing NCCT by Ϸ90% (PϽ0.001), whereas the 564DϾH mutant had no significantly inhibitory effect on flux through NCCT. In oocytes expressing ROMK, wild-type WNK4 produced Ͼ50% inhibition of steady-state current through ROMK at a ϩ20-mV holding potential (PϽ0.001). The 564DϾH mutant produced further inhibition with steady-state currents to some 60% to 70% of those seen with the wild-type WNK4. Using fluorescent-tagged NCCT (enhanced cyan fluorescent protein-NCCT) and ROMK (enhanced green fluorescent protein-ROMK) to quantify the expression of the proteins in the oocyte membrane, it appears that the functional effects of the 564DϾH mutation can be explained by alteration in the surface expression of NCCT and ROMK. Compared with wild-type WNK4, WNK4 564DϾH causes increased cell surface expression of NCCT but reduced expression of ROMK. This work confirms that the novel missense mutation in WNK4, 564DϾH, is functionally active and highlights further how switching charge on a single residue in the acid motif of WNK4 affects its interaction with the thiazide-sensitive target NCCT and the potassium channel ROMK.

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The Syndrome of Hypertension and Hyperkalaemia without Renal Failure: Long Term Correction by Thiazide Diuretic

Cited by 58 publications

References 2 publications

Racial Difference in the Activity of the Amiloride-Sensitive Epithelial Sodium Channel

Racial Difference in the Activity of the Amiloride-Sensitive Epithelial Sodium Channel

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

A New Kindred With Pseudohypoaldosteronism Type II and a Novel Mutation (564D>H) in the Acidic Motif of the WNK4 Gene

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