A molecular update on pseudohypoaldosteronism type II

Pathare, Ganesh; Hoenderop, Joost G. J.; Bindels, René J. M.; San‐Cristobal, Pedro

doi:10.1152/ajprenal.00440.2013

Cited by 47 publications

(44 citation statements)

References 88 publications

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“…Specific mutations in WNK1 or WNK4 cause FHHt, a hereditary disease characterized by hypertension, and hyperkalemia (65,98). Both kinases have important roles in regulating Na ϩ transporters in the ASDN, including NCC and ENaC (29,32,37,41,69,84,98,102,104).…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in WNK1, WNK4, or their cognate E3 ubiquitin ligase complex Kelch-like 3/Cullin 3 cause familial hyperkalemic hypertension (FHHt; also referred to as pseudohyopaldosteronism type II) (5,49,98). FHHt is a hereditary disease characterized by hypertension, hyperkalemia, and hyperchloremic metabolic acidosis with normal or slightly elevated aldosterone levels (65,98). A growing body of evidence implicates WNK kinases in differentiating between the state of volume depletion, where the aldosterone-sensitive distal nephron must enhance the reabsorption of both Na ϩ and Cl Ϫ , from that of hyperkalemia, where the primary need is to enhance renal K ϩ secretion, facilitated by Na ϩ absorption via ENaC.…”

mentioning

confidence: 99%

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Cell-specific regulation of L-WNK1 by dietary K⁺

Webb

Carrisoza-Gaytán

Montalbetti

et al. 2016

American Journal of Physiology-Renal Physiology

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Flow-induced K+ secretion in the aldosterone-sensitive distal nephron is mediated by high-conductance Ca2+-activated K+ (BK) channels. Familial hyperkalemic hypertension (pseudohypoaldosteronism type II) is an inherited form of hypertension with decreased K+ secretion and increased Na+ reabsorption. This disorder is linked to mutations in genes encoding with-no-lysine kinase 1 (WNK1), WNK4, and Kelch-like 3/Cullin 3, two components of an E3 ubiquitin ligase complex that degrades WNKs. We examined whether the full-length (or “long”) form of WNK1 (L-WNK1) affected the expression of BK α-subunits in HEK cells. Overexpression of L-WNK1 promoted a significant increase in BK α-subunit whole cell abundance and functional channel expression. BK α-subunit abundance also increased with coexpression of a kinase dead L-WNK1 mutant (K233M) and with kidney-specific WNK1 (KS-WNK1), suggesting that the catalytic activity of L-WNK1 was not required to increase BK expression. We examined whether dietary K+ intake affected L-WNK1 expression in the aldosterone-sensitive distal nephron. We found a paucity of L-WNK1 labeling in cortical collecting ducts (CCDs) from rabbits on a low-K+ diet but observed robust staining for L-WNK1 primarily in intercalated cells when rabbits were fed a high-K+ diet. Our results and previous findings suggest that L-WNK1 exerts different effects on renal K+ secretory channels, inhibiting renal outer medullary K+ channels and activating BK channels. A high-K+ diet induced an increase in L-WNK1 expression selectively in intercalated cells and may contribute to enhanced BK channel expression and K+ secretion in CCDs.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Cell-specific regulation of L-WNK1 by dietary K⁺

Webb

Carrisoza-Gaytán

Montalbetti

et al. 2016

American Journal of Physiology-Renal Physiology

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“…Similarly, the disease-causing KLHL3 mutations are missense mutations, generating KLHL3 that cannot interact with either CUL3 or WNK kinases (depending on the site of the mutation). This provides a plausible hypothesis for the disease pathogenesis: increased WNK kinase abundance activates SPAK and NCC (1).…”

Section: Introductionmentioning

confidence: 94%

“…Familial hyperkalemic hypertension (FHHt; also called pseudohypoaldosteronism type II) is a rare monogenic disease characterized by hyperkalemia and hypertension (1). The disease can result from mutations in 4 genes: the atypical kinases WNK1 and WNK4, and the cullin RING ligase (CRL) family members kelchlike 3 (KLHL3) and cullin 3 (CUL3).…”

Section: Introductionmentioning

confidence: 99%

Hyperkalemic hypertension–associated cullin 3 promotes WNK signaling by degrading KLHL3

et al. 2014

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“…The symptoms usually start in the neonatal period or early infancy and consist of salt wasting, hyperkalemia, metabolic acidosis, dehydration, and failure to thrive. Table 2 summarizes the different types of PHA (5)(6)(7)(8)(9). All patients with type 3 PHA have abnormal urinary tract anatomy and/or bacterial UTI (8,9 ).…”

Section: Discussionmentioning

confidence: 99%

A 5-Week-Old Boy with Failure to Thrive, Marked Hyperkalemia, and Hyponatremia

Blasi

Dickerson

et al. 2016

Clinical Chemistry

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A 5-week-old white boy presented to the emergency department after referral from his primary care physician with concerns for failure to thrive.The patient's birth weight was 2892 g at 37 weeks of gestation (10th percentile). He was 2665 g at 5 weeks of age (Ͻsecond percentile). He had been exclusively breastfed for the first 3 weeks of his life. At 3 weeks of age, he was introduced to a bottle with expressed breast milk but showed little interest in the bottle. At a well-child checkup at 4 weeks of age, his weight was down, and formula supplementation was recommended. In the last 3 days before the admission, he had been lethargic and had difficulty feeding. He had 2 episodes of projectile vomiting during that week. There was a noticeable reduction in the amount of stool and urine output during the last 2 days before admission, without fever or diarrhea.The patient was born at 37 weeks of gestation by spontaneous vaginal delivery. Mother was found to be group B Streptococcus (GBS) 5 positive but was not treated before delivery, so the patient was monitored for 48 h in the hospital before being discharged home. Mother also had a history of bilateral vesicoureteral reflux and reimplantation surgery. There was no other history of genital, urinary, or kidney abnormalities.On exam, the patient was cachectic and lethargic but did have warm extremities, brisk capillary refill (Ͻ2 s), and good distal pulses. No skin hyperpigmentation was seen and the genitalia were normal. Laboratory tests were significant for potassium 10.2 mmol/L, sodium 116 mmol/L, chloride 91 mmol/L, blood urea nitrogen (BUN)64 mg/dL (22.9 mmol/L), creatinine 0.7 mg/dL (61.9 mol/L), glucose 88 mg/dL (4.9 mmol/L), pH 7.29, CO 2 pressure (PCO 2 ) 29 mmHg, and total CO 2 15.0 mmol/L ( Table 1). The specimen was not hemolyzed. Contamination of the sample with potassium was originally suspected by the medical technologist. Communication with clinical staff confirmed the quality of the sample. Electrocardiogram showed no electrolyterelated changes. The patient's blood pressure was 75/41 mmHg (normal interval 65-85/45-55 mmHg). The patient received normal saline boluses to supplement sodium, kayexalate to chelate potassium, and calcium gluconate to antagonize the membrane actions of hyperkalemia. Although he had 2 normal newborn screens, the possibility of congenital adrenal hyperplasia (CAH) was still in the differential diagnoses owing to such high potassium and low sodium. The patient was started on stress-dose steroids after measurement of baseline adrenocorticotropic hormone (ACTH), renin, aldosterone, 17-hydroxyprogesterone (17-OHP), and cortisol. Urinalysis for the possibility of urinary tract infection (UTI) was also performed. One hour later, sodium increased to 125 mmol/L and potassium decreased to 7.9 mmol/L. The patient was admitted to the neonatal intensive care unit for further evaluation and management. CASE RESOLUTIONOn the second day of admission, cortisol was increased at 38.3 g/dL (1057 nmol/L), and 17-OHP was 29 ng/dL (0.88 nmol/L) (Tab...

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A molecular update on pseudohypoaldosteronism type II

Cited by 47 publications

References 88 publications

Cell-specific regulation of L-WNK1 by dietary K⁺

Cell-specific regulation of L-WNK1 by dietary K⁺

Hyperkalemic hypertension–associated cullin 3 promotes WNK signaling by degrading KLHL3

A 5-Week-Old Boy with Failure to Thrive, Marked Hyperkalemia, and Hyponatremia

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A molecular update on pseudohypoaldosteronism type II

Cited by 47 publications

References 88 publications

Cell-specific regulation of L-WNK1 by dietary K+

Cell-specific regulation of L-WNK1 by dietary K+

Hyperkalemic hypertension–associated cullin 3 promotes WNK signaling by degrading KLHL3

A 5-Week-Old Boy with Failure to Thrive, Marked Hyperkalemia, and Hyponatremia

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Cell-specific regulation of L-WNK1 by dietary K⁺

Cell-specific regulation of L-WNK1 by dietary K⁺