| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Endocrine Care |
Department of Medicine E (H.M., M.M., M.T.-W., R.P., Z.F.), Institute of Endocrinology (I.V.), and Laboratory of Biochemical Pharmacology (Z.F.), Sheba Medical Center, Tel Aviv University, Tel Hashomer 52621, Israel
Address all correspondence and requests for reprints to: Zvi Farfel, M.D., Department of Medicine E, Sheba Medical Center, Tel Hashomer 52621, Israel. E-mail: . farfel{at}ccsg.tau.ac.il
Abstract
Mutations in WNK kinases cause pseudohypoaldosteronism type II (PHA II) and may represent a novel signaling pathway regulating blood pressure and K+ and H+ homeostasis. PHA II is an autosomal dominant disorder characterized by hypertension, hyperkalemia, and metabolic acidosis, with normal glomerular filtration rate. Thiazide diuretics correct all abnormalities. Inactivating mutations in the thiazide-sensitive NaCl cotransporter cause Gitelman syndrome, featuring hypotension, hypokalemia, and metabolic alkalosis plus hypocalciuria and hypomagnesemia. We investigated whether hypercalciuria and hypermagnesemia occurred in a large family with PHA II. Eight affected and eight unaffected members of a PHA II family with the Q565E WNK 4 mutation were studied. In affected members blood and urinary chemistry were measured on and off hydrochlorothiazide (HCTZ), and bone mineral density was determined. Marked sensitivity to HCTZ was found. A mean dose of 20 mg/d reduced mean blood pressure in the six hypertensive subjects by 54.3 (systolic) and 24.5 (diastolic) mm Hg. In affected subjects, HCTZ reduced mean serum K+ by 1.12 mmol/liter, mean serum Cl- by 6.2 mmol/liter, and mean urinary calcium by 65% and elevated mean serum calcium by 0.11 mmol/liter and mean serum urate by 118 µmol/liter. Compared with the literature, this represents an increase of 6–7 in HCTZ potency. Affected members had normomagnesemia, hypercalciuria (336 ± 113 vs. 155 ± 39 mg/d in unaffected relatives, P = 0.0002), and decreased bone mineral density. In PHA II the observed marked sensitivity to thiazides and the hypercalciuria are consistent with increased NaCl cotransporter activity. PHA II may serve as a model to investigate thiazides’ beneficial effects and side effects.
THE MOLECULAR DEFECTS underlying several monogenic forms of hypertension have been identified during recent years (1), enhancing our understanding of essential hypertension. The recent discovery that mutations in WNK kinases cause the autosomal dominant disease pseudohypoaldosteronism type II (PHA II) has renewed interest in this entity (2). PHA II, also known as familial hyperkalemia and hypertension (3), is characterized by hyperkalemia, hypertension, metabolic acidosis, and low renin, with normal glomerular filtration rate (3, 4). Thiazide diuretics reverse all abnormalities (3, 4). Inactivating mutations in the thiazide-sensitive NaCl cotransporter (NCCT) cause Gitelman syndrome (GS) (5). Patients with GS display opposite features to PHA II, namely hypokalemia, hypotension, metabolic alkalosis, and high renin (6, 7), plus hypocalciuria and hypomagnesemia (8). We therefore tested the hypothesis that patients with PHA II have, in addition, hypercalciuria and hypermagnesemia. In affected members of a family with PHA II, with the Q565E mutation in WNK 4 (2), which we have been following for more than 25 yr (3, 9, 10), we discontinued hydrochlorothiazide (HCTZ) for the study and witnessed a marked sensitivity to the drug on its resumption. In affected family members, hypercalciuria was found, accompanied by a low bone mineral density, but serum magnesium concentrations were found to be normal.
Subjects and Methods
The kindred was described by us in the past (3, 9, 10). DNA was used for linkage analysis and identification of the mutant gene [K 13 in (2, 11)]. In the six affected members who were treated by HCTZ, the drug was discontinued for 2 wk. In two affected members who were not receiving thiazides, HCTZ was given at doses of 6.25–25 mg/d, each dose for 2 wk, to test its hypocalciuric effect. One affected member who had been treated by chlorothiazide 500 mg daily died before commencement of the current study. Fasting chemical blood variables were measured in the remaining eight affected members on and off thiazides. Urinary 24-h collections were obtained in the eight affected members, on and off thiazides, and in eight of their unaffected family members (subjects III 2, IV 1, IV 4, IV 5, IV 6, V 1, V 2, V 3; Fig. 1
), whose mean age was 23.5 ± 13.4 yr, with a range of 11–45 yr. Affectation status was determined clinically as well as by genotype analysis (2). Free dietary calcium intake was allowed. Dietary calcium intake was determined by dietary history taking. Affected family members had a bone mineral densitometry study using dual-energy x-ray absorptiometry (Lunar Corp., Madison, WI). Data are presented as mean ± SD. For comparison between means, the nonparametric Mann-Whitney statistical test was used. Two-tailed P values are reported. The study was approved by the local ethics committee of the Sheba Medical Center (Tel Hashomer, Israel).
|
The pedigree of the family is shown in Fig. 1
, and clinical details are presented in Table 1. Genotype analysis discovered the substitution of glutamate for glutamine at codon 565 of the WNK 4 kinase only in the affected members of the family. Unaffected relatives did not have the Q565E mutation (2). All affected members had hyperkalemia in the range of 5.5–6.1 mmol/liter, accompanied by hyperchloremia of 108–113 mmol/liter and acidosis with bicarbonate levels of 21–24 mmol/liter (10). Blood pressure was elevated in seven subjects, two of whom (II 1, II 3) each had cerebrovascular accident and coronary disease. Subject II 1 died at 62 yr of acute myocardial infarction. Necropsy revealed diffuse arteriosclerosis with nephrosclerosis and normal adrenal glands. Subjects IV 2 and IV 3 were found to be hyperkalemic at the ages of 10 and 4 yr, respectively (10), and were found to be hypertensive at the ages of 27 and 18 yr, respectively. Two subjects, III 6 and III 8, were normotensive at the ages of 49 and 40 yr, respectively. Subject IV 3 had transient growth retardation at the age of 11 yr. Thiazides were started, and the patient resumed normal growth. Thiazides were administered for 17–32 yr in four subjects, for 7–8 yr in two subjects, and for 2 yr in one subject. The thiazides were well tolerated in all subjects. The two normotensive patients were not treated by the drug. Thiazides were administered as HCTZ, at a daily dose of 25 mg in four subjects and 12.5 mg in two subjects. Patient II 1 was treated by chlorothiazide 500 mg/d. Dietary calcium intake ranged between 400 and 1200 mg/d; five subjects consumed less than 700 mg/d. Mean urinary calcium excretion off thiazides was 321 ± 110 mg/d, with a range of 228–560 mg/d (Table 1).
|
). In the six hypertensive patients, stopping thiazide therapy caused a rise in mean systolic blood pressure from 135.8 ± 12.4 to 180.1 ± 22.4 mm Hg (P = 0.0022) and mean diastolic blood pressure from 80.2 ± 3.6 to 104.7 ± 7.5 mm Hg (P = 0.0022). In the two normotensive subjects, HCTZ at doses of 6.25–25 mg/d further reduced blood pressure to 100–110/75–80 mm Hg.
|
and Fig. 2a), with mean levels falling from 5.73 ± 0.18 to 4.61 ± 0.19 mmol/liter (P = 0.0002), a mean reduction of 1.12 mmol/liter. In the two normotensive subjects, we observed a dose-response effect; raising thiazide dose increased the potassium-lowering effect (Fig. 2a). HCTZ decreased mean serum Cl- from 110.2 ± 1.4 to 104.0 ± 0.6 mmol (P = 0.0002; Table 2 and Fig. 2b), a mean reduction of 6.2 mmol/liter. Serum calcium rose in all subjects from a mean of 2.38 ± 0.05 to 2.49 ± 0.10 mmol/liter (P = 0.015; Table 2 and Fig. 2c). A marked rise in serum urate was observed in all subjects, from a mean of 190 ± 54 to 308 ± 89 µmol/liter (P = 0.015), an increment of 118 µmol/liter. In the two normotensive subjects, a dose-response effect was observed (Table 2 and Fig. 2d). Mean serum urea rose from 5.46 ± 1.79 to 6.75 ± 1.66 mmol/liter (P = 0.083). Serum magnesium concentrations were normal in the basal state and did not change with thiazides. The concentrations of serum Na+ and creatinine were not changed significantly by HCTZ. Serum glucose rose from a mean of 5.03 ± 0.87 to 5.63 ± 1.24 mmol/liter (P = 0.13). A rise occurred in six of the subjects (Table 2 and Fig. 2e). Although mean serum cholesterol did not rise significantly, in three subjects it rose by 1.0–1.8 mmol/liter (Table 2 and Fig. 2f). Mean low-density lipoprotein cholesterol increased by 0.47 mmol/liter (Table 2 and Fig. 2g); however, it was not statistically significant. The rise in serum calcium was not accompanied by a change in PTH levels, which were 40.6 ± 13.8 at the basal state and 38 ± 13.8 pg/ml on thiazides (P = 0.50). The 25 (OH) vitamin D and 1,25 (OH)2 vitamin D levels at the basal state were normal (Table 2).
|
. Basal urinary calcium levels were significantly higher than those values on thiazide therapy (336 ± 113 vs. 113 ± 65 mg/d, P = 0.0002) and 0.85 ± 0.34 vs. 0.28 ± 0.19 mmol/mmol creatinine, (P = 0.001). Thiazide therapy was associated with a 65% reduction in 24-h urinary calcium excretion. In a few patients, the reduction was dramatic, reaching more than 90% in one patient (IV 3). Figure 2, h and i, shows individual response of urinary calcium. In affected members the urinary excretion of Mg2+, Na+, K+, Cl-, PO43-, and urate, measured on thiazides, was not different than the basal values.
Hypercalciuria was found in all affected members (Table 1). They fulfilled the criteria of hypercalciuria as defined by Breslau (12), namely urinary calcium excretion of more than 300 mg/d in males, more than 250 mg/d in females, or more than 4 mg/kg per d in either sex while on a random diet, and a urinary excretion of more than 200 mg/d on a calcium-restricted (400 mg/d) diet. The basal calcium excretion in affected family members was significantly higher than that of their eight unaffected relatives (336 ± 113 vs. 155 ± 39 mg/d, P = 0.0002, and 0.85 ± 0.34 vs. 0.40 ± 0.21 mmol/mmol creatinine, P = 0.003; Table 3). Because of the structure of the pedigree, the unaffected relatives were younger than the affected members whose mean age was 50.2 ± 17.7 yr. Magnesium urinary excretion was not different in affected members, compared with unaffected relatives. In affected members the urinary excretion of Na+, K+, Cl-, PO43-, and urate was not different statistically, compared with unaffected family members (Table 3).
|
). At any site, a Z-score reduction of 1.0 or more was found in seven members, Z-score reduction of 2.0 or more was found in four subjects, and a Z-score reduction of 3.0 or more was found in two subjects. These Z-score values are in the range reported by Reed et al. (13) for familial hypercalciuria. Moreover, vertebral fractures were found in two subjects. Although three subjects had other medical conditions that may contribute to decreased BMD (state post partial gastrectomy, early menopause, and ulcerative colitis in complete prolonged remission), no such explanation was found in the remainder, and it is possible that the basic metabolic defect was responsible for the decreased bone mineral density. Interestingly, nephrolithiasis was not a prominent feature in this hypercalciuric kindred. One affected member had renal colic before initiation of thiazide therapy (Table 1).
|
The identification in PHA II of disease-specific mutations in the genes that encode the WNK 1 and WNK 4 protein kinases, which are specifically expressed in the distal nephron, has disclosed a new cellular signaling pathway that regulates blood pressure and electrolyte homeostasis (2). However, the details of the components and mechanisms of this pathway are currently unknown. The clinical observation that in PHA II hypertension is accompanied by hyperkalemia, rather than by hypokalemia, which occurs in all other forms of monogenic hypertension and is the result of activation of the renal epithelial sodium channel (1), highlights the need for more complete clinical investigation of the disease.
The molecular target of WNK kinase is not known. Because thiazide diuretics ameliorate the abnormal manifestations of PHA II and inactivating mutations in thiazides’ molecular target, NCCT, were identified in GS, which displays phenotypic opposite features to those of PHA II, we tested the hypothesis that patients with PHA II have hypercalciuria and hypermagnesemia, opposite to the hypocalciuria and hypomagnesemia present in GS. The temporary cessation of thiazide diuretics enabled us to witness a very marked sensitivity to thiazides in PHA II. Of the eight living family members, the six hypertensive subjects have been treated successfully for decades by a mean daily dose of 20 mg HCTZ. This dose produced a potent hypotensive effect, accompanied by marked reductions in serum K+ and Cl- and rises in serum Ca2+ and urate. Although no formal dose-response study was done to compare PHA II with normal subjects or with hypertensive patients, data from other studies are available for comparison. Carlsen et al. (14) administered the thiazide bendrofluazide at daily doses equivalent to 25–200 mg HCTZ to patients with essential hypertension. Bendrofluazide at a daily dose of 1.25 mg, equivalent to 25 mg HCTZ, reduced serum K+ by 0.16 mmol/liter. A similar HCTZ dose in our study reduced serum K+ by 1.12 mmol/liter. Assuming a linear dose-response relationship, a relative HCTZ potency of 6–7 may be calculated. A similar relative potency of HCTZ in PHA II was observed also for the hyperuricemic effect. Bendrofluazide at equivalent daily dose of 25 mg HCTZ produced a rise of 19 µmol/liter in serum urate (14), compared with the serum urate rise of 118 µmol/liter we observed in PHA II, a 6- to 7-fold ratio. In hypercalciuric stone formers, Nicar et al. (15) found that HCTZ administration at a mean daily dose of about 80 mg produced a mean rise in serum calcium levels of 0.05 mmol/liter, compared with the rise of 0.11 mmol/liter in serum calcium observed in our patients, using about a third of this dose. Assuming dose-response linearity, we obtain in PHA II a relative HCTZ potency of six. The increased sensitivity to thiazides probably means that the consequences of the molecular defect are specifically corrected by thiazides. The use of thiazides in essential hypertension is apparently less specific. HCTZ at a dose equivalent to what we used produced a much smaller reduction in blood pressure than what we observed [systolic 13 and diastolic 10 mm Hg in (14), compared with 45 and 25 mm Hg, respectively, we observed in PHA II].
PHA II may therefore serve as a model for the investigation of thiazide action and side effects. Important are the controversial issues of thiazide-induced hyperglycemia and hypercholesterolemia (16, 17). In our affected family members, we have found a rise in mean serum glucose of 0.6 mmol/liter with thiazide treatment, with a rise occurring in six of the eight subjects. Total cholesterol levels rose by a mean of 0.5 mmol/liter, but this was observed mainly in three subjects (all overweight, two of them postmenopausal women) in whom it rose by 1.0–1.8 mmol/liter. Low-density lipoprotein cholesterol rose by about 10%. The hypothesis that hypokalemia is responsible for the thiazide-induced hyperglycemia and hypercholesterolemia (18) is not supported by our findings because no hypokalemic values were achieved. In addition, we found no correlation between the hypercholesterolemic and the hyperglycemic effects among our subjects. These issues have great importance in the face of the current decline in the use of thiazides in the treatment of essential hypertension, mainly because of the concern about their adverse effects on lipid profiles and glucose levels (16, 17, 18, 19).
Although theoretically the previous exposure to thiazides could affect sensitivity to thiazides even 2 wk after their cessation, this is unlikely because similar thiazide effects were observed both in the six subjects with previous thiazide exposure and in the two subjects without such exposure. The mechanism of the marked sensitivity of PHA II to thiazides is not clear. It is obvious that thiazides have target-related as well as nontarget-related side effects. Thiazide effect is not just the production of a GS-like state because there is no hyperglycemia or hypercholesterolemia in GS. A better understanding of the biochemical signal transduction pathway, involving WNK kinase and NCCT, will probably shed light on the beneficial effects and side effects of thiazides.
In an effort to extend the analogy of PHA II as a mirror image of GS, we measured serum and urinary Mg2+ and Ca2+concentration in our family. Normomagnesemia rather than the expected hypermagnesemia was found. Thiazides did not change serum Mg2+, and urinary Mg2+ excretion was similar in affected and unaffected members. In contrast, hypercalciuria was found in all affected subjects. Affected family members had significantly higher urinary calcium excretion rates than their unaffected relatives. Because in PHA II the hypercalciuria appears to be only mild to moderate, it may escape notice. Indeed in an extensive review of the clinical features of PHA II, hypercalciuria is not mentioned (4), although in two unrelated children with PHA II, one of them normotensive, hypercalciuria did occur (20, 21). In our family the hypocalciuric effect of HCTZ was very marked, with treatment producing a mean reduction of 65% in urinary calcium excretion. This hypocalciuric effect is similar in magnitude to that observed in idiopathic hypercalciuria, although in the latter state, higher thiazide doses are usually used (15). The hypocalciuric effect in PHA II is much higher than that observed in normal subjects. HCTZ at 50 mg daily caused a 20% reduction in urinary calcium in healthy subjects (22). The 3-fold higher hypocalciuric effect in PHA II at half-dose of HCTZ is consistent with a 6-fold increased sensitivity to thiazides in PHA II, assuming a linear relationship between dose and response.
Because hypercalciuric patients are prone to develop decreased BMD because of the negative calcium balance (23), we measured BMD in our kindred. A definite, in some cases marked, decrease in BMD was found. All subjects had a decrease in BMD in at least one site of at least 0.9 Z-score units. In four subjects it was 2.0 Z-score units or more, and two subjects had a decrease of 3.0 Z-score units or more. Although three subjects had other potentially contributing medical conditions, none could be identified in the rest. Moreover, vertebral fractures were found in two subjects. A possible etiology for the hypercalciuria and decreased BMD is the acidosis that accompanies PHA II (24); however, in affected family members, it was mild. It is interesting that in GS there is hypocalciuria, but in its closely related entity, Bartter syndrome, with a similar degree of alkalosis, there is hypercalciuria (8). A possible role for the acidosis in the pathogenesis of the hypercalciuria and bone loss in PHA II cannot be ruled out. Alternatively, the basic metabolic defect in PHA II could be causing both hypercalciuria and, indirectly or even in a direct way, the bone loss. Indeed, NCCT is expressed in bone, and HCTZ inhibits bone resorption by isolated rat osteoclasts (25). We suggest that BMD and urinary calcium excretion be monitored in patients with PHA II. It is possible that hypercalciuria contributed to the transient growth retardation in subject IV 3. Indeed, short stature was reported in PHA II (4). Thiazide therapy in PHA II patients may therefore be beneficial to bones in addition to its effects on blood pressure (26). Of note is that increased BMD was recently reported to be present in GS (27), representing another example of the clinically opposite features of PHA II and GS.
The marked sensitivity to thiazides in PHA II supports the notion that NCCT is constitutively activated in this condition. This contrasts the blunted response to thiazides observed in GS (28). This hypothesis of constitutive activation of NCCT in PHA II is also supported by the finding of hypercalciuria in PHA II because in the distal convoluted tubule in which NCCT is expressed, sodium and calcium absorption are inversely related (29). The mechanism of the lack of Mg2+ retention in PHA II remains unknown. Because the mechanism of the Mg2+ wasting in GS or in NCCT knockout mice (30) remains poorly understood (31), the effect of mutations causing constitutive activation of NCCT on Mg2+ balance cannot be predicted with certainty.
All affected members of our family had hyperkalemia, hypertension occurred in only seven members, and two members were normotensive at ages 40 and 49 yr. Indeed in another kindred, with WNK 4 mutation R1185C, hyperkalemia without hypertension occurred in four family members, the oldest being 37 yr old when reported (32). Therefore, although the gene mutation appears to be constantly associated with hyperkalemia, the development of hypertension is not a universal finding in PHA II and presumably depends on other genetic or environmental factors. More genotype-phenotype studies in PHA II are needed to clarify this and other phenotypic diversity in PHA II, such as the acidosis that may vary in severity between families with mutations in WNK 4 and WNK 1 kinases (33). The elucidation of the WNK kinase pathway and the identification of defective genes in other families with PHA II will shed further light on the new cellular signaling pathway and may contribute to our understanding of essential hypertension.
Acknowledgments
We thank the family members for their cooperation. We also thank Prof. Y. Weisman (Bone Unit, Tel Aviv Medical Center) for performing the vitamin D assays.
Footnotes
Abbreviations: BMD, Bone mineral density; GS, Gitelman syndrome; HCTZ, hydrochlorothiazide; NCCT, NaCl cotransporter; PHA II, pseudohypoaldosteronism type II.
Received October 18, 2001.
Accepted January 24, 2002.
References
This article has been cited by other articles:
 |
|
 |
|
  A. Ohta, T. Rai, N. Yui, M. Chiga, S.-S. Yang, S.-H. Lin, E. Sohara, S. Sasaki, and S. Uchida Targeted disruption of the Wnk4 gene decreases phosphorylation of Na-Cl cotransporter, increases Na excretion and lowers blood pressure Hum. Mol. Genet., October 15, 2009; 18(20): 3978 - 3986. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Gamba The thiazide-sensitive Na+-Cl- cotransporter: molecular biology, functional properties, and regulation by WNKs Am J Physiol Renal Physiol, October 1, 2009; 297(4): F838 - F848. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Ahlstrom and A. S. L. Yu Characterization of the kinase activity of a WNK4 protein complex Am J Physiol Renal Physiol, September 1, 2009; 297(3): F685 - F692. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Mayan, S. Melnikov, I. Novikov, E. J. Holtzman, and Z. Farfel Familial Hyperkalemia and Hypertension: Pathogenetic Insights Based on Lithium Clearance J. Clin. Endocrinol. Metab., August 1, 2009; 94(8): 3010 - 3016. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. H. Ellison and J. Loffing Thiazide Effects and Adverse Effects: Insights From Molecular Genetics Hypertension, August 1, 2009; 54(2): 196 - 202. [Full Text] [PDF]
|
|
|
|
|
|
W. Zhang, T. Na, and J.-B. Peng WNK3 positively regulates epithelial calcium channels TRPV5 and TRPV6 via a kinase-dependent pathway Am J Physiol Renal Physiol, November 1, 2008; 295(5): F1472 - F1484. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Richardson and D. R. Alessi The regulation of salt transport and blood pressure by the WNK-SPAK/OSR1 signalling pathway J. Cell Sci., October 15, 2008; 121(20): 3293 - 3304. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. San-Cristobal, J. Ponce-Coria, N. Vazquez, N. A. Bobadilla, and G. Gamba WNK3 and WNK4 amino-terminal domain defines their effect on the renal Na+-Cl- cotransporter Am J Physiol Renal Physiol, October 1, 2008; 295(4): F1199 - F1206. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. McCormick, C.-L. Yang, and D. H. Ellison WNK Kinases and Renal Sodium Transport in Health and Disease: An Integrated View Hypertension, March 1, 2008; 51(3): 588 - 596. [Full Text] [PDF]
|
|
|
|
 |
|
 H. Mayan, D. Attar-Herzberg, M. Shaharabany, E. J Holtzman, and Z. Farfel Increased urinary Na-Cl cotransporter protein in familial hyperkalaemia and hypertension Nephrol. Dial. Transplant., February 1, 2008; 23(2): 492 - 496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-B. Peng and D. G. Warnock WNK4-mediated regulation of renal ion transport proteins Am J Physiol Renal Physiol, October 1, 2007; 293(4): F961 - F973. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Dvorak, C. De Joussineau, D. H. Carter, T. Pisitkun, M. A. Knepper, G. Gamba, P. J. Kemp, and D. Riccardi Thiazide Diuretics Directly Induce Osteoblast Differentiation and Mineralized Nodule Formation by Interacting with a Sodium Chloride Co-Transporter in Bone J. Am. Soc. Nephrol., September 1, 2007; 18(9): 2509 - 2516. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Jiang, W. B. Ferguson, and J.-B. Peng WNK4 enhances TRPV5-mediated calcium transport: potential role in hypercalciuria of familial hyperkalemic hypertension caused by gene mutation of WNK4 Am J Physiol Renal Physiol, February 1, 2007; 292(2): F545 - F554. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. Golbang, G. Cope, A. Hamad, M. Murthy, C.-H. Liu, A. W. Cuthbert, and K. M. O'Shaughnessy Regulation of the expression of the Na/Cl cotransporter by WNK4 and WNK1: evidence that accelerated dynamin-dependent endocytosis is not involved Am J Physiol Renal Physiol, December 1, 2006; 291(6): F1369 - F1376. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Pacheco-Alvarez, P. S. Cristobal, P. Meade, E. Moreno, N. Vazquez, E. Munoz, A. Diaz, M. E. Juarez, I. Gimenez, and G. Gamba The Na+:Cl- Cotransporter Is Activated and Phosphorylated at the Amino-terminal Domain upon Intracellular Chloride Depletion J. Biol. Chem., September 29, 2006; 281(39): 28755 - 28763. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Moreno, P. S. Cristobal, M. Rivera, N. Vazquez, N. A. Bobadilla, and G. Gamba Affinity-defining Domains in the Na-Cl Cotransporter: A DIFFERENT LOCATION FOR Cl- AND THIAZIDE BINDING J. Biol. Chem., June 23, 2006; 281(25): 17266 - 17275. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Fu, A. Subramanya, D. Rozansky, and D. M. Cohen WNK kinases influence TRPV4 channel function and localization Am J Physiol Renal Physiol, June 1, 2006; 290(6): F1305 - F1314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Gamba TRPV4: a new target for the hypertension-related kinases WNK1 and WNK4 Am J Physiol Renal Physiol, June 1, 2006; 290(6): F1303 - F1304. [Full Text] [PDF]
|
|
|
|
|
|
A. S. L. Yu WNK signaling in the distal tubule: an inhibitory cascade regulating salt transport Am J Physiol Renal Physiol, March 1, 2006; 290(3): F617 - F618. [Full Text] [PDF]
|
|
|
|
 |
|
 A. Lazrak, Z. Liu, and C.-L. Huang Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms PNAS, January 31, 2006; 103(5): 1615 - 1620. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. B. N. Lee, E. Huang, and H. J. Ward Tight junction biology and kidney dysfunction Am J Physiol Renal Physiol, January 1, 2006; 290(1): F20 - F34. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Hadchouel, C. Delaloy, S. Faure, J.-M. Achard, and X. Jeunemaitre Familial Hyperkalemic Hypertension J. Am. Soc. Nephrol., January 1, 2006; 17(1): 208 - 217. [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Tobin, S. M. Raleigh, S. Newhouse, P. Braund, C. Bodycote, J. Ogleby, D. Cross, J. Gracey, S. Hayes, T. Smith, et al. Association of WNK1 Gene Polymorphisms and Haplotypes With Ambulatory Blood Pressure in the General Population Circulation, November 29, 2005; 112(22): 3423 - 3429. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. Golbang, M. Murthy, A. Hamad, C.-H. Liu, G. Cope, W. Van't Hoff, A. Cuthbert, and K. M. O'Shaughnessy A New Kindred With Pseudohypoaldosteronism Type II and a Novel Mutation (564D>H) in the Acidic Motif of the WNK4 Gene Hypertension, August 1, 2005; 46(2): 295 - 300. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B.-e Xu, S. Stippec, P.-Y. Chu, A. Lazrak, X.-J. Li, B.-H. Lee, J. M. English, B. Ortega, C.-L. Huang, and M. H. Cobb WNK1 activates SGK1 to regulate the epithelial sodium channel PNAS, July 19, 2005; 102(29): 10315 - 10320. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Newhouse, C. Wallace, R. Dobson, C. Mein, J. Pembroke, M. Farrall, D. Clayton, M. Brown, N. Samani, A. Dominiczak, et al. Haplotypes of the WNK1 gene associate with blood pressure variation in a severely hypertensive population from the British Genetics of Hypertension study Hum. Mol. Genet., July 1, 2005; 14(13): 1805 - 1814. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Gamba Molecular Physiology and Pathophysiology of Electroneutral Cation-Chloride Cotransporters Physiol Rev, April 1, 2005; 85(2): 423 - 493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Gamba Role of WNK kinases in regulating tubular salt and potassium transport and in the development of hypertension Am J Physiol Renal Physiol, February 1, 2005; 288(2): F245 - F252. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Naray-Fejes-Toth, P. M. Snyder, and G. Fejes-Toth The kidney-specific WNK1 isoform is induced by aldosterone and stimulates epithelial sodium channel-mediated Na+ transport PNAS, December 14, 2004; 101(50): 17434 - 17439. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. D Hughes How do thiazide and thiazide-like diuretics lower blood pressure? Journal of Renin-Angiotensin-Aldosterone System, December 1, 2004; 5(4): 155 - 160. [Abstract] [PDF]
|
|
|
|
|
|
H. Mayan, G. Munter, M. Shaharabany, M. Mouallem, R. Pauzner, E. J. Holtzman, and Z. Farfel Hypercalciuria in Familial Hyperkalemia and Hypertension Accompanies Hyperkalemia and Precedes Hypertension: Description of a Large Family with the Q565E WNK4 Mutation J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 4025 - 4030. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Moreno, C. Tovar-Palacio, P. de los Heros, B. Guzman, N. A. Bobadilla, N. Vazquez, D. Riccardi, E. Poch, and G. Gamba A Single Nucleotide Polymorphism Alters the Activity of the Renal Na+:Cl- Cotransporter and Reveals a Role for Transmembrane Segment 4 in Chloride and Thiazide Affinity J. Biol. Chem., April 16, 2004; 279(16): 16553 - 16560. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Konrad, K. P. Schlingmann, and T. Gudermann Insights into the molecular nature of magnesium homeostasis Am J Physiol Renal Physiol, April 1, 2004; 286(4): F599 - F605. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Faure, C. Delaloy, V. Leprivey, J. Hadchouel, D. G. Warnock, X. Jeunemaitre, and J.-M. Achard WNK kinases, distal tubular ion handling and hypertension Nephrol. Dial. Transplant., December 1, 2003; 18(12): 2463 - 2467. [Full Text] [PDF]
|
|
|
|
|
|
D. H. Ellison The Thiazide-Sensitive Na-Cl Cotransporter and Human Disease: Reemergence of an Old Player J. Am. Soc. Nephrol., February 1, 2003; 14(2): 538 - 540. [Full Text] [PDF]
|
|
|
|
|
|
F. H. Wilson, K. T. Kahle, E. Sabath, M. D. Lalioti, A. K. Rapson, R. S. Hoover, S. C. Hebert, G. Gamba, and R. P. Lifton Molecular pathogenesis of inherited hypertension with hyperkalemia: The Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4 PNAS, January 21, 2003; 100(2): 680 - 684. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Pratt, W. T. Ambrosius, R. Agarwal, G. J. Eckert, and S. Newman Racial Difference in the Activity of the Amiloride-Sensitive Epithelial Sodium Channel Hypertension, December 1, 2002; 40(6): 903 - 908. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
