Read by QxMD icon Read


Eduardo R Argaiz, Maria Chavez-Canales, Mauricio Ostrosky-Frid, Alejandro Rodriguez-Gama, Norma Vázquez, Xochiquetzal Gonzalez-Rodriguez, Jesus Garcia-Valdés, Juliette Hadchouel, David H Ellison, Gerardo Gamba
Familial Hyperkalemic Hypertension (FHHt) can be mainly attributed to increased activity of the renal Na+:Cl- cotransporter (NCC), which is caused by altered expression and regulation of the WNK1 and WNK4 kinases. The WNK1 gene gives rise to a kidney-specific isoform that lacks the kinase domain (KS-WNK1), the expression of which occurs primarily in the distal convoluted tubule. The role played by KS-WNK1 in the modulation of the WNK/SPAK/NCC pathway remains elusive. In the present study, we assessed the effect of human KS-WNK1 on NCC activity and on the WNK4-SPAK pathway...
May 30, 2018: American Journal of Physiology. Renal Physiology
Chloé Rafael, Christelle Soukaseum, Véronique Baudrie, Perrine Frère, Juliette Hadchouel
Mutations of the gene encoding WNK1 [With No lysine (K) kinase 1] or WNK4 cause Familial Hyperkalemic Hypertension (FHHt). Previous studies have shown that the activation of SPAK (Ste20-related Proline/Alanine-rich Kinase) plays a dominant role in the development of FHHt caused by WNK4 mutations. The implication of SPAK in FHHt caused by WNK1 mutation has never been investigated. To clarify this issue, we crossed WNK1+/FHHt mice with SPAK knock-in mice in which the T-loop Thr243 residue was mutated to alanine to prevent activation by WNK kinases...
February 19, 2018: Scientific Reports
Mohammed Zubaerul Ferdaus, James A McCormick
Autosomal dominant mutations in Cullin3 (Cul3) cause the most severe form of Familial Hyperkalemic Hypertension (FHHt). Cul3 mutations cause skipping of exon 9 which results in an internal deletion of 57 amino acids from the CUL3 protein (CUL3-∆9). The precise mechanism by which this altered form of CUL3 causes FHHt is controversial. CUL3 is a member of the Cullin-Ring ubiquitin Ligase (CRL) family which mediates ubiquitination and thus degradation of cellular proteins including With-no-lysine [K] kinases (WNKs)...
January 17, 2018: American Journal of Physiology. Renal Physiology
Orit Kliuk-Ben Bassat, Vered Carmon, Aaron Hanukoglu, Liat Ganon, Eias Massalha, Eliezer J Holtzman, Zvi Farfel, Haim Mayan
BACKGROUND: Familial hyperkalemia and hypertension (FHHt) is an inherited disorder manifested by hyperkalemia and hypertension. The following four causative genes were identified: WNK1, WNK4, CUL3, and KLHL3. For the first 3 genes, inheritance is autosomal dominant. For KLHL3, inheritance is mostly dominant. A few cases with autosomal recessive disease were described. The mechanism of these 2 modes of inheritance is not clear. In the recessive form, the phenotype of heterozygotes is not well described...
2017: Nephron
P Richard Grimm, Richard Coleman, Eric Delpire, Paul A Welling
Aberrant activation of with no lysine (WNK) kinases causes familial hyperkalemic hypertension (FHHt). Thiazide diuretics treat the disease, fostering the view that hyperactivation of the thiazide-sensitive sodium-chloride cotransporter (NCC) in the distal convoluted tubule (DCT) is solely responsible. However, aberrant signaling in the aldosterone-sensitive distal nephron (ASDN) and inhibition of the potassium-excretory renal outer medullary potassium (ROMK) channel have also been implicated. To test these ideas, we introduced kinase-activating mutations after Lox-P sites in the mouse Stk39 gene, which encodes the terminal kinase in the WNK signaling pathway, Ste20-related proline-alanine-rich kinase (SPAK)...
September 2017: Journal of the American Society of Nephrology: JASN
Meena Murthy, Thimo Kurz, Kevin M O'Shaughnessy
Hypertension (high blood pressure) is a major public health problem affecting more than a billion people worldwide with complications, including stroke, heart failure and kidney failure. The regulation of blood pressure is multifactorial reflecting genetic susceptibility, in utero environment and external factors such as obesity and salt intake. In keeping with Arthur Guyton's hypothesis, the kidney plays a key role in blood pressure control and data from clinical studies; physiology and genetics have shown that hypertension is driven a failure of the kidney to excrete excess salt at normal levels of blood pressure...
April 2017: Cellular and Molecular Life Sciences: CMLS
Richard Hollander, Geert Mortier, Koen van Hoeck
Hyperkalemia in young children is a rare phenomenon and in many cases caused by hemolysis in the specimen due to difficulties in obtaining a sample. However, hyperkalemia can also be a sign of a rare Mendelian syndrome known as familial hyperkalemic hypertension or pseudohypoaldosteronism type II. This disease is characterized by hyperkalemia, hypertension, and mild hyperchloremic metabolic acidosis (with normal anion gap) despite normal glomerular filtration. Full recovery of these abnormalities with thiazide diuretics is essential not to miss the diagnosis of this syndrome...
December 2016: European Journal of Pediatrics
C Rafael, W Abdel Khalek, I Kouranti, E Clauser, X Jeunemaitre, J Hadchouel
OBJECTIVE: Familial Hyperkalemic Hypertension (FHHt) is caused by mutations in WNK1, WNK4, KLHL3 or CUL3 (cullin-3). Patients with CUL3 mutation display a more severe phenotype. The mechanisms associated with this severity remain unclear. DESIGN AND METHOD: All CUL3 mutations result in the skipping of exon 9. We have generated a mouse model of "Cul3-FHHt" by deleting Cul3 exon 9. RESULTS: RT-PCR proved that the exon skipping occurred as expected in the kidney of Cul3+/d9 mice...
September 2016: Journal of Hypertension
Meena Murthy, Thimo Kurz, Kevin M O'Shaughnessy
Familial hyperkalemic hypertension (FHHt) is a rare inherited form of salt-dependent hypertension caused by mutations in proteins that regulate the renal Na(+)-Cl(-) cotransporter NCC Mutations in four genes have been reported to cause FHHt including CUL3 (Cullin3) that encodes a component of a RING E3 ligase. Cullin-3 binds to WNK kinase-bound KLHL3 (the substrate recognition subunit of the ubiquitin ligase complex) to promote ubiquitination and proteasomal degradation of WNK kinases. Deletion of exon 9 from CUL3 (affecting residues 403-459, CUL3(Δ403-459)) causes a severe form of FHHt (PHA2E) that is recapitulated closely in a knock-in mouse model...
July 2016: Physiological Reports
Mohammed Z Ferdaus, James A McCormick
Chronic high blood pressure (hypertension) is the most common disease in the Unites States. While several classes of drugs exist to treat it, many patients (up to 10 million Americans) respond poorly to therapy, even when multiple classes are used. Recent evidence suggests that a significant portion of patients will always remain hypertensive despite maximum therapy with the drugs currently available. Therefore, there is a pressing need to develop novel antihypertensive agents. One limitation has been the identification of new targets, a limitation that has been overcome by recent insights into the mechanisms underlying monogenic forms of hypertension...
June 1, 2016: American Journal of Physiology. Renal Physiology
Chloé Rafael, Maria Chavez-Canales, Juliette Hadchouel
The study of Familial Hyperkalemic Hypertension (FHHt), a rare monogenic disease, allowed remarkable advances in the understanding of the mechanisms of regulation of NaCl reabsorption by the distal nephron. FHHt results from mutations in the genes encoding WNK1 and WNK4, two serine-threonine kinases of the WNK (With No lysine [K]) family. The clinical manifestations of FHHt are due, among others, to an increased activity of the Na(+)-Cl(-) cotransporter NCC. Several groups therefore tried to understand how WNK1 and WNK4 could regulate NCC...
March 2016: Médecine Sciences: M/S
Chong Zhang, Nicholas P Meermeier, Andrew S Terker, Katharina I Blankenstein, Jeffrey D Singer, Juliette Hadchouel, David H Ellison, Chao-Ling Yang
Mutations in WNK1 and WNK4, and in components of the Cullin-Ring Ligase system, kelch-like 3 (KLHL3) and Cullin 3 (CUL3), can cause the rare hereditary disease, Familial Hyperkalemic Hypertension (FHHt). The disease is characterized by overactivity of the renal sodium chloride cotransporter (NCC), which is phosphorylated and activated by the WNK-stimulated Ste20-type kinases, SPAK and OSR1. WNK kinases themselves can be targeted for ubiquitination and degradataion by the CUL3-KLHL3 E3 ubiquitin ligase complex...
January 1, 2016: Biochemical and Biophysical Research Communications
Frances-Rose Schumacher, Keith Siew, Jinwei Zhang, Clare Johnson, Nicola Wood, Sarah E Cleary, Raya S Al Maskari, James T Ferryman, Iris Hardege, Yasmin, Nichola L Figg, Radoslav Enchev, Axel Knebel, Kevin M O'Shaughnessy, Thimo Kurz
Deletion of exon 9 from Cullin-3 (CUL3, residues 403-459: CUL3(Δ403-459)) causes pseudohypoaldosteronism type IIE (PHA2E), a severe form of familial hyperkalaemia and hypertension (FHHt). CUL3 binds the RING protein RBX1 and various substrate adaptors to form Cullin-RING-ubiquitin-ligase complexes. Bound to KLHL3, CUL3-RBX1 ubiquitylates WNK kinases, promoting their ubiquitin-mediated proteasomal degradation. Since WNK kinases activate Na/Cl co-transporters to promote salt retention, CUL3 regulates blood pressure...
October 2015: EMBO Molecular Medicine
H Louis Dit Picard, S Latreche, N Thurairajasingam, C Auzan, B Fiquet, R Frayssinet, A Garnier, V Jendruchova, T Lobbedez, L Martorell, G Mortier, I Pela, S Taque, R Vargas-Poussou, E Clauser, X Jeunemaitre
OBJECTIVE: Familial hyperkalaemic hypertension (FHHt) also known as Gordon syndrome is a rare form of hypertension. DESIGN AND METHOD: In 2001, WNK1 and WNK4, have been identified as responsible for this syndrome, regulating the ion transport in the kidney. In 2012, an American laboratory as well as ours, have identified two other genes, KLHL3 and CUL3 as responsible for the disease. These two unexpected genes are part of an E3-ubiquitin-ligase complex involved in the degradation of target proteins after ubiquitination, among them the WNK1 and WNK4 kinases...
June 2015: Journal of Hypertension
H Louis Dit Picard, N Thurairajasingam, S Decramer, X Girerd, K Oshaugnessy, P Mulatero, G Roussey, I Tack, R Unwin, R Vargas-Poussou, X Jeunemaitre
OBJECTIVE: Mutations in the WNK1 and WNK4 genes have been shown to cause Familial Hyperkalemic Hypertension (FHHt, OMIM #145260), an inherited disorder combining arterial hypertension and hyperkalemia with metabolic acidosis. More recently, mutations in the KLHL3-CUL3 E3 ubiquitin ligase complex have shed light on the importance of the With-No-Lysine kinases (WNKs) cellular degradation on ion transport. DESIGN AND METHOD: Here we identified a new form of autosomal dominant hyperkalemic tubular acidosis with normal blood pressure caused by missense mutations in the WNK1 gene...
June 2015: Journal of Hypertension
Haim Mayan, Vered Carmon, Kira Oleinikov, Shira London, Raphael Halevy, Eliezer J Holtzman, Yardena Tenenbaum-Rakover, Zvi Farfel, Aaron Hanukoglu
BACKGROUND: Familial hyperkalemia and hypertension (FHHt) is a rare genetic disorder manifested by hyperkalemia and early hypertension. Hypercalciuria is another accompanying feature. Mutations in WNK4 and WNK1 were found initially, and recently additional mutations were found in two genes, KLHL3 and CUL3, which are components of the Ubiquitin system. It was not reported whether these latter mutations are accompanied by hypercalciuria. METHODS: We compared urinary calcium excretion (UCa) in affected subjects with FHHt and KLHL3 mutations, and in their unaffected family members, and in affected subjects with FHHt and WNK4 Q565E mutation...
2015: Nephron
James A McCormick, Chao-Ling Yang, Chong Zhang, Brittney Davidge, Katharina I Blankenstein, Andrew S Terker, Bethzaida Yarbrough, Nicholas P Meermeier, Hae J Park, Belinda McCully, Mark West, Aljona Borschewski, Nina Himmerkus, Markus Bleich, Sebastian Bachmann, Kerim Mutig, Eduardo R Argaiz, Gerardo Gamba, Jeffrey D Singer, David H Ellison
Familial hyperkalemic hypertension (FHHt) is a monogenic disease resulting from mutations in genes encoding WNK kinases, the ubiquitin scaffold protein cullin 3 (CUL3), or the substrate adaptor kelch-like 3 (KLHL3). Disease-associated CUL3 mutations abrogate WNK kinase degradation in cells, but it is not clear how mutant forms of CUL3 promote WNK stability. Here, we demonstrated that an FHHt-causing CUL3 mutant (CUL3 Δ403-459) not only retains the ability to bind and ubiquitylate WNK kinases and KLHL3 in cells, but is also more heavily neddylated and activated than WT CUL3...
November 2014: Journal of Clinical Investigation
María Chávez-Canales, Chong Zhang, Christelle Soukaseum, Erika Moreno, Diana Pacheco-Alvarez, Emmanuelle Vidal-Petiot, María Castañeda-Bueno, Norma Vázquez, Lorena Rojas-Vega, Nicholas P Meermeier, Shaunessy Rogers, Xavier Jeunemaitre, Chao-Ling Yang, David H Ellison, Gerardo Gamba, Juliette Hadchouel
The with-no-lysine (K) kinases, WNK1 and WNK4, are key regulators of blood pressure. Their mutations lead to familial hyperkalemic hypertension (FHHt), associated with an activation of the Na-Cl cotransporter (NCC). Although it is clear that WNK4 mutants activate NCC via Ste20 proline-alanine-rich kinase, the mechanisms responsible for WNK1-related FHHt and alterations in NCC activity are not as clear. We tested whether WNK1 modulates NCC through WNK4, as predicted by some models, by crossing our recently developed WNK1-FHHt mice (WNK1(+/FHHt)) with WNK4(-/-) mice...
November 2014: Hypertension
Mark Glover, James S Ware, Amanda Henry, Martin Wolley, Roddy Walsh, Louise V Wain, Shengxin Xu, William G Van't Hoff, Martin D Tobin, Ian P Hall, Stuart Cook, Richard D Gordon, Michael Stowasser, Kevin M O'Shaughnessy
The study of families with rare inherited forms of hypo- and hyper-tension has been one of the most successful strategies to probe the molecular pathophysiology of blood pressure control and has revealed dysregulation of distal nephron Na+ reabsorption to be a common mechanism. FHHt (familial hyperkalaemic hypertension; also known as Gordon's syndrome) is a salt-dependent form of hypertension caused by mutations in the regulators of the thiazide-sensitive Na+-Cl- co-transporter NCC [also known as SLC12A3 (solute carrier family 12 member 3)] and is effectively treated by thiazide diuretics and/or dietary salt restriction...
May 2014: Clinical Science (1979-)
Ganesh Pathare, Joost G J Hoenderop, René J M Bindels, Pedro San-Cristobal
The DCT (distal convoluted tubule) is the site of microregulation of water reabsorption and ion handling in the kidneys, which is mainly under the control of aldosterone. Aldosterone binds to and activates mineralocorticoid receptors, which ultimately lead to increased sodium reabsorption in the distal part of the nephron. Impairment of mineralocorticoid signal transduction results in resistance to aldosterone and mineralocorticoids, and, therefore, causes disturbances in electrolyte balance. Pseudohypoaldosteronism type II (PHAII) or familial hyperkalemic hypertension (FHHt) is a rare, autosomal dominant syndrome characterized by hypertension, hyperkalemia, metabolic acidosis, elevated or low aldosterone levels, and decreased plasma renin activity...
December 1, 2013: American Journal of Physiology. Renal Physiology
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"