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Yongfeng Gong, Jianghui Hou
Claudins are discovered to be key players in renal epithelial physiology. They are involved in developmental, physiological, and pathophysiological differentiation. In the glomerular podocytes, claudin-1 is an important determinant of cell junction fate. In the proximal tubule, claudin-2 plays important roles in paracellular salt reabsorption. In the thick ascending limb, claudin-14, -16, and -19 regulate the paracellular reabsorption of calcium and magnesium. Recessive mutations in claudin-16 or -19 cause an inherited calcium and magnesium losing disease...
November 23, 2016: Pflügers Archiv: European Journal of Physiology
Marie Mitani, Munehiro Furuichi, Satoshi Narumi, Tomonobu Hasegawa, Motoko Chiga, Shinichi Uchida, Seiji Sato
Pseudohypoaldosteronism type II (PHA II) is a renal tubular disease that causes hyperkalemia, hypertension, and metabolic acidosis. Mutations in four genes (WNK4, WNK1, KLHL3, and CUL3) are known to cause PHA II. We report a patient with PHA II carrying a KLHL3 mutation, who also had congenital hypopituitarism. The patient, a 3-yr-old boy, experienced loss of consciousness at age 10 mo. He exhibited growth failure, hypertension, hyperkalemia, and metabolic acidosis. We diagnosed him as having PHA II because he had low plasma renin activity with normal plasma aldosterone level and a low transtubular potassium gradient...
October 2016: Clinical Pediatric Endocrinology: Case Reports and Clinical Investigations: Official Journal of the Japanese Society for Pediatric Endocrinology
Lingyun Wang, Ji-Bin Peng
Interaction between the acidic motif (AM) of protein kinase WNK4 and the Kelch domain of KLHL3 are involved in the pathogenesis of pseudohypoaldosteronism type II, a hereditary form of hypertension. This interaction is disrupted by some disease-causing mutations in either WNK4 or KLHL3, or by angiotensin II- and insulin-induced phosphorylation of KLHL3 at serine 433, which is also a site frequently mutated in patients. However, the mechanism by which this phosphorylation disrupts the interaction is unclear...
October 11, 2016: Protein Science: a Publication of the Protein Society
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...
September 17, 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
D Kelly, M R Rodzlan, X Jeunemaitre, C Wall
No abstract text is available yet for this article.
July 2016: QJM: Monthly Journal of the Association of Physicians
Juliette Hadchouel, David H Ellison, Gerardo Gamba
The discovery of four genes responsible for pseudohypoaldosteronism type II, or familial hyperkalemic hypertension, which features arterial hypertension with hyperkalemia and metabolic acidosis, unmasked a complex multiprotein system that regulates electrolyte transport in the distal nephron. Two of these genes encode the serine-threonine kinases WNK1 and WNK4. The other two genes [kelch-like 3 (KLHL3) and cullin 3 (CUL3)] form a RING-type E3-ubiquitin ligase complex that modulates WNK1 and WNK4 abundance. WNKs regulate the activity of the Na(+):Cl(-) cotransporter (NCC), the epithelial sodium channel (ENaC), the renal outer medullary potassium channel (ROMK), and other transport pathways...
2016: Annual Review of Physiology
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
Yuya Araki, Tatemitsu Rai, Eisei Sohara, Takayasu Mori, Yuichi Inoue, Kiyoshi Isobe, Eriko Kikuchi, Akihito Ohta, Sei Sasaki, Shinichi Uchida
Pseudohypoaldosteronism type II (PHAII) is a hereditary hypertensive disease caused by mutations in four different genes: with-no-lysine kinases (WNK) 1 and 4, Kelch-like family member 3 (KLHL3), and cullin 3 (Cul3). Cul3 and KLHL3 form an E3 ligase complex that ubiquitinates and reduces the expression level of WNK4. PHAII-causing mutations in WNK4 and KLHL3 impair WNK4 ubiquitination. However, the molecular pathogenesis of PHAII caused by Cul3 mutations is unclear. In cultured cells and human leukocytes, PHAII-causing Cul3 mutations result in the skipping of exon 9, producing mutant Cul3 protein lacking 57 amino acids...
2015: Biology Open
Yuki Yoshizaki, Yutaro Mori, Yoshihito Tsuzaki, Takayasu Mori, Naohiro Nomura, Mai Wakabayashi, Daiei Takahashi, Moko Zeniya, Eriko Kikuchi, Yuya Araki, Fumiaki Ando, Kiyoshi Isobe, Hidenori Nishida, Akihito Ohta, Koichiro Susa, Yuichi Inoue, Motoko Chiga, Tatemitsu Rai, Sei Sasaki, Shinichi Uchida, Eisei Sohara
Mutations in with-no-lysine kinase (WNK) 1, WNK4, Kelch-like 3 (KLHL3), and Cullin3 result in an inherited hypertensive disease, pseudohypoaldosteronism type II. WNK activates the Na-Cl cotransporter (NCC), increasing sodium reabsorption in the kidney. Further, KLHL3, an adapter protein of Cullin3-based E3 ubiquitin ligase, has been recently found to bind to WNK, thereby degrading them. Insulin and vasopressin have been identified as powerful activators of WNK signaling. In this study, we investigated effects of Akt and PKA, key downstream substrates of insulin and vasopressin signaling, respectively, on KLHL3...
November 13, 2015: Biochemical and Biophysical Research Communications
Yutaro Mori, Takayasu Mori, Mai Wakabayashi, Yuki Yoshizaki, Moko Zeniya, Eisei Sohara, Tatemitsu Rai, Shinichi Uchida
We reported that kelch-like protein 3 (KLHL3)-Cullin3 E3 ligase ubiquitinates with-no-lysine kinase 4 (WNK4) and that impaired WNK4 ubiquitination causes pseudohypoaldosteronism type II, a hereditary hypertensive disease. However, we also found that KLHL3-induced WNK4 degradation could not be inhibited completely by a proteasome inhibitor. Rather, on exposure, for 24 h, of HEK293T cells expressing WNK4 and KLHL3 to a proteasome inhibitor, epoxomicin, the WNK4 protein level was further decreased. As proteasome inhibition is known to activate p62-mediated selective autophagy, we investigated whether WNK4 degradation induced by KLHL3 is also mediated by such an autophagic mechanism...
November 15, 2015: Biochemical Journal
Alan X Ji, Anh Chu, Tine Kragh Nielsen, Samir Benlekbir, John L Rubinstein, Gilbert G Privé
Cullin3 (Cul3)-based ubiquitin E3 ligase complexes catalyze the transfer of ubiquitin from an E2 enzyme to target substrate proteins. In these assemblies, the C-terminal region of Cul3 binds Rbx1/E2-ubiquitin, while the N-terminal region interacts with various BTB (bric-à-brac, tramtrack, broad complex) domain proteins that serve as substrate adaptors. Previous crystal structures of the homodimeric BTB proteins KLHL3, KLHL11 and SPOP in complex with the N-terminal domain of Cul3 revealed the features required for Cul3 recognition in these proteins...
January 16, 2016: Journal of Molecular Biology
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...
August 18, 2015: EMBO Molecular Medicine
Eisei Sohara, Shinichi Uchida
Pseudohypoaldosteronism type II (PHAII) is a hereditary disease characterized by salt-sensitive hypertension, hyperkalemia and thiazide sensitivity. Mutations in with-no-lysine kinase 1 (WNK1) and WNK4 genes are reported to cause PHAII. Rigorous studies have demonstrated that WNK kinases constitute a signaling cascade with oxidative stress-responsive gene 1 (OSR1), Ste20-related proline-alanine-rich kinase (SPAK) and the solute carrier family 12a (SLC12a) transporter, including thiazide-sensitive NaCl cotransporter...
September 2016: Nephrology, Dialysis, Transplantation
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
Yongfeng Gong, Jinzhi Wang, Jing Yang, Ernie Gonzales, Ronaldo Perez, Jianghui Hou
A rare Mendelian syndrome--pseudohypoaldosteronism type II (PHA-II)--features hypertension, hyperkalemia, and metabolic acidosis. Genetic linkage studies and exome sequencing have identified four genes--with no lysine kinase 1 (wnk1), wnk4, Kelch-like 3 (KLHL3), and Cullin 3 (Cul3)--mutations of which all caused PHA-II phenotypes. The previous hypothesis was that the KLHL3-Cul3 ubiquitin complex acted on the wnk4-wnk1 kinase complex to regulate Na(+)/Cl(-) cotransporter (NCC) mediated salt reabsorption in the distal tubules of the kidney...
April 7, 2015: Proceedings of the National Academy of Sciences of the United States of America
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