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Dídac Casas-Alba, Jordi Vila Cots, Laura Monfort Carretero, Loreto Martorell Sampol, Maria-Christina Zennaro, Xavier Jeunemaitre, Juan Antonio Camacho Díaz
Pseudohypoaldosteronism (PHA) comprises a diverse group of rare diseases characterized by sodium and potassium imbalances incorrectly attributed to a defect in aldosterone production. Two different forms of PHA have been described, type I (PHAI) and type II (PHAII). PHAI has been subclassified into renal and systemic. Given the rarity and heterogeneity of this group of disorders we report three patients who carry PHA and a brief revision of current literature focused on the comparative analysis of PHAI and PHAII...
May 1, 2017: Journal of Pediatric Endocrinology & Metabolism: JPEM
#22
JOURNAL ARTICLE
Mari Ishigami-Yuasa, Yuko Watanabe, Takayasu Mori, Hiroyuki Masuno, Shinya Fujii, Eriko Kikuchi, Shinichi Uchida, Hiroyuki Kagechika
Pseudohypoaldosteronism type II (PHAII) is characterized by hyperkalemia and hypertension despite a normal glomerular filtration rate. Abnormal activation of the signal cascade of with-no-lysine kinase (WNK) with OSR1 (oxidative stress-responsive kinase 1)/SPAK (STE20/SPS1-related proline/alanine-rich kinase) and NCC (NaCl cotransporter) results in characteristic salt-sensitive hypertension. Thus, inhibitors of the WNK-OSR1/SPAK-NCC cascade are candidates for a new class of antihypertensive drugs. In this study, we developed novel inhibitors of this signal cascade from the 9-aminoacridine lead compound 1, one of the hit compounds obtained by screening our chemical library for WNK-SPAK binding inhibitors...
July 15, 2017: Bioorganic & Medicinal Chemistry
#23
JOURNAL ARTICLE
Yuri Kasagi, Daiei Takahashi, Tomomi Aida, Hidenori Nishida, Naohiro Nomura, Moko Zeniya, Takayasu Mori, Emi Sasaki, Fumiaki Ando, Tatemitsu Rai, Shinichi Uchida, Eisei Sohara
Mutations in the with-no-lysine kinase 1 (WNK1), WNK4, Kelch-like 3 (KLHL3), and Cullin3 (CUL3) genes were identified as being responsible for hereditary hypertensive disease pseudohypoaldosteronism type II (PHAII). Normally, the KLHL3/CUL3 ubiquitin ligase complex degrades WNKs. In PHAII, the loss of interaction between KLHL3 and WNK4 increases levels of WNKs because of impaired ubiquitination, leading to abnormal over-activation of the WNK-OSR1/SPAK-NCC cascade in the kidney's distal convoluted tubules (DCT)...
May 27, 2017: Biochemical and Biophysical Research Communications
#24
JOURNAL ARTICLE
Chengbiao Zhang, Lijun Wang, Xiao-Tong Su, Junhui Zhang, Dao-Hong Lin, Wen-Hui Wang
Mice transgenic for genomic segments harboring PHAII (pseudohypoaldosteronism type II) mutant Wnk4 (with-No-Lysine kinase 4) (TgWnk4PHAII ) have hyperkalemia which is currently believed to be the result of high activity of Na-Cl cotransporter (NCC). This leads to decreasing Na+ delivery to the distal nephron segment including late distal convoluted tubule (DCT) and connecting tubule (CNT). Since epithelial Na+ channel (ENaC) and renal outer medullary K+ channel (ROMK or Kir4.1) are expressed in the late DCT and play an important role in mediating K+ secretion, the aim of the present study is to test whether ROMK and ENaC activity in the DCT/CNT are also compromised in the mice expressing PHAII mutant Wnk4...
April 1, 2017: American Journal of Physiology. Renal Physiology
#25
JOURNAL ARTICLE
Emi Sasaki, Koichiro Susa, Takayasu Mori, Kiyoshi Isobe, Yuya Araki, Yuichi Inoue, Yuki Yoshizaki, Fumiaki Ando, Yutaro Mori, Shintaro Mandai, Moko Zeniya, Daiei Takahashi, Naohiro Nomura, Tatemitsu Rai, Shinichi Uchida, Eisei Sohara
Mutations in the with-no-lysine kinase 1 ( WNK1 ), WNK4 , kelch-like 3 ( KLHL3 ), and cullin3 ( CUL3 ) genes are known to cause the hereditary disease pseudohypoaldosteronism type II (PHAII). It was recently demonstrated that this results from the defective degradation of WNK1 and WNK4 by the KLHL3/CUL3 ubiquitin ligase complex. However, the other physiological in vivo roles of KLHL3 remain unclear. Therefore, here we generated KLHL3 -/- mice that expressed β-galactosidase (β-Gal) under the control of the endogenous KLHL3 promoter...
April 1, 2017: Molecular and Cellular Biology
#26
JOURNAL ARTICLE
Larry N Agbor, Stella-Rita C Ibeawuchi, Chunyan Hu, Jing Wu, Deborah R Davis, Henry L Keen, Frederick W Quelle, Curt D Sigmund
Cullin-3 ( CUL3 ) mutations ( CUL3 Δ 9 ) were previously identified in hypertensive patients with pseudohypoaldosteronism type-II (PHAII), but the mechanism causing hypertension and whether this is driven by renal tubular or extratubular mechanisms remains unknown. We report that selective expression of CUL3Δ9 in smooth muscle acts by interfering with expression and function of endogenous CUL3, resulting in impaired turnover of the CUL3 substrate RhoA, increased RhoA activity, and augmented RhoA/Rho kinase signaling...
November 17, 2016: JCI Insight
#27
JOURNAL ARTICLE
P W Crous, M J Wingfield, D M Richardson, J J Le Roux, D Strasberg, J Edwards, F Roets, V Hubka, P W J Taylor, M Heykoop, M P Martín, G Moreno, D A Sutton, N P Wiederhold, C W Barnes, J R Carlavilla, J Gené, A Giraldo, V Guarnaccia, J Guarro, M Hernández-Restrepo, M Kolařík, J L Manjón, I G Pascoe, E S Popov, M Sandoval-Denis, J H C Woudenberg, K Acharya, A V Alexandrova, P Alvarado, R N Barbosa, I G Baseia, R A Blanchette, T Boekhout, T I Burgess, J F Cano-Lira, A Čmoková, R A Dimitrov, M Yu Dyakov, M Dueñas, A K Dutta, F Esteve-Raventós, A G Fedosova, J Fournier, P Gamboa, D E Gouliamova, T Grebenc, M Groenewald, B Hanse, G E St J Hardy, B W Held, Ž Jurjević, T Kaewgrajang, K P D Latha, L Lombard, J J Luangsa-Ard, P Lysková, N Mallátová, P Manimohan, A N Miller, M Mirabolfathy, O V Morozova, M Obodai, N T Oliveira, M E Ordóñez, E C Otto, S Paloi, S W Peterson, C Phosri, J Roux, W A Salazar, A Sánchez, G A Sarria, H-D Shin, B D B Silva, G A Silva, M Th Smith, C M Souza-Motta, A M Stchigel, M M Stoilova-Disheva, M A Sulzbacher, M T Telleria, C Toapanta, J M Traba, N Valenzuela-Lopez, R Watling, J Z Groenewald
Novel species of fungi described in the present study include the following from Australia: Vermiculariopsiella eucalypti, Mulderomyces natalis (incl. Mulderomyces gen. nov.), Fusicladium paraamoenum, Neotrimmatostroma paraexcentricum, and Pseudophloeospora eucalyptorum on leaves of Eucalyptus spp., Anungitea grevilleae (on leaves of Grevillea sp.), Pyrenochaeta acaciae (on leaves of Acacia sp.), and Brunneocarpos banksiae (incl. Brunneocarpos gen. nov.) on cones of Banksia attenuata. Novel foliicolous taxa from South Africa include Neosulcatispora strelitziae (on Strelitzia nicolai), Colletotrichum ledebouriae (on Ledebouria floridunda), Cylindrosympodioides brabejum (incl...
June 2016: Persoonia
#28
JOURNAL ARTICLE
Adriana Mercado, Paola de Los Heros, Zesergio Melo, María Chávez-Canales, Adrián R Murillo-de-Ozores, Erika Moreno, Silvana Bazúa-Valenti, Norma Vázquez, Juliette Hadchouel, Gerardo Gamba
The K(+)-Cl(-) cotransporters (KCC1-KCC4) encompass a branch of the SLC12 family of electroneutral cation-coupled chloride cotransporters that translocate ions out of the cell to regulate various factors, including cell volume and intracellular chloride concentration, among others. L-WNK1 is an ubiquitously expressed kinase that is activated in response to osmotic stress and intracellular chloride depletion, and it is implicated in two distinct hereditary syndromes: the renal disease pseudohypoaldosteronism type II (PHAII) and the neurological disease hereditary sensory neuropathy 2 (HSN2)...
July 1, 2016: American Journal of Physiology. Cell Physiology
#29
JOURNAL ARTICLE
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...
October 21, 2015: Biology Open
#30
REVIEW
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
#31
REVIEW
Silvana Bazúa-Valenti, Gerardo Gamba
The renal thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC) is the salt transporter in the distal convoluted tubule. Its activity is fundamental for defining blood pressure levels. Decreased NCC activity is associated with salt-remediable arterial hypotension with hypokalemia (Gitelman disease), while increased activity results in salt-sensitive arterial hypertension with hyperkalemia (pseudohypoaldosteronism type II; PHAII). The discovery of four different genes causing PHAII revealed a complex multiprotein system that regulates the activity of NCC...
May 15, 2015: American Journal of Physiology. Cell Physiology
#32
JOURNAL ARTICLE
Moko Zeniya, Nobuhisa Morimoto, Daiei Takahashi, Yutaro Mori, Takayasu Mori, Fumiaki Ando, Yuya Araki, Yuki Yoshizaki, Yuichi Inoue, Kiyoshi Isobe, Naohiro Nomura, Katsuyuki Oi, Hidenori Nishida, Sei Sasaki, Eisei Sohara, Tatemitsu Rai, Shinichi Uchida
Recently, the kelch-like protein 3 (KLHL3)-Cullin3 complex was identified as an E3 ubiquitin ligase for with no lysine (WNK) kinases, and the impaired ubiquitination of WNK4 causes pseudohypoaldosteronism type II (PHAII), a hereditary hypertensive disease. However, the involvement of WNK kinase regulation by ubiquitination in situations other than PHAII has not been identified. Previously, we identified the WNK3-STE20/SPS1-related proline/alanine-rich kinase-Na/K/Cl cotransporter isoform 1 phosphorylation cascade in vascular smooth muscle cells and found that it constitutes an important mechanism of vascular constriction by angiotensin II (AngII)...
September 2015: Journal of the American Society of Nephrology: JASN
#33
REVIEW
Shinichi Uchida
PURPOSE OF REVIEW: Efforts to explore the pathogenic mechanisms underlying hereditary hypertension caused by a single gene mutation have brought about conceptual advances in our understanding of blood pressure regulation. We here discuss a novel pathogenic mechanism underlying the hereditary hypertensive disease pseudohypoaldosteronism type II (PHAII), caused by mutations in three different genes encoding for Cullin-3, Kelch-like protein 3 (KLHL3), and with-no-lysine kinases (WNKs). RECENT FINDINGS: In 2001, mutations in genes encoding for WNKs were identified as being responsible for PHAII...
September 2014: Current Opinion in Nephrology and Hypertension
#34
JOURNAL ARTICLE
Koichiro Susa, Eisei Sohara, Tatemitsu Rai, Moko Zeniya, Yutaro Mori, Takayasu Mori, Motoko Chiga, Naohiro Nomura, Hidenori Nishida, Daiei Takahashi, Kiyoshi Isobe, Yuichi Inoue, Kenta Takeishi, Naoki Takeda, Sei Sasaki, Shinichi Uchida
Pseudohypoaldosteronism type II (PHAII) is a hereditary disease characterized by salt-sensitive hypertension, hyperkalemia and metabolic acidosis, and genes encoding with-no-lysine kinase 1 (WNK1) and WNK4 kinases are known to be responsible. Recently, Kelch-like 3 (KLHL3) and Cullin3, components of KLHL3-Cullin3 E3 ligase, were newly identified as responsible for PHAII. We have reported that WNK4 is the substrate of KLHL3-Cullin3 E3 ligase-mediated ubiquitination. However, WNK1 and Na-Cl cotransporter (NCC) were also reported to be a substrate of KLHL3-Cullin3 E3 ligase by other groups...
October 1, 2014: Human Molecular Genetics
#35
JOURNAL ARTICLE
Daiei Takahashi, Takayasu Mori, Naohiro Nomura, Muhammad Zakir Hossain Khan, Yuya Araki, Moko Zeniya, Eisei Sohara, Tatemitsu Rai, Sei Sasaki, Shinichi Uchida
By analysing the pathogenesis of a hereditary hypertensive disease, PHAII (pseudohypoaldosteronism type II), we previously discovered that WNK (with-no-lysine kinase)-OSR1/SPAK (oxidative stress-responsive 1/Ste20-like proline/alanine-rich kinase) cascade regulates NCC (Na-Cl co-transporter) in the DCT (distal convoluted tubules) of the kidney. However, the role of WNK4 in the regulation of NCC remains controversial. To address this, we generated and analysed WNK4-/- mice. Although a moderate decrease in SPAK phosphorylation and a marked increase in WNK1 expression were evident in the kidneys of WNK4-/- mice, the amount of phosphorylated and total NCC decreased to almost undetectable levels, indicating that WNK4 is the major WNK positively regulating NCC, and that WNK1 cannot compensate for WNK4 deficiency in the DCT...
2014: Bioscience Reports
#36
REVIEW
Ana Cristina Andérica-Romero, Laura Escobar, Teresa Padilla-Flores, José Pedraza-Chaverri
One of the most important systems for protein degradation is the ubiquitin-proteasome system (UPS). The highly specific process called ubiquitination is provided by the E3 ubiquitin ligases, which mediates degradation via the proteasome system. The ubiquitin ligases based on cullins are the type of ubiquitin ligases known so far. The complex based on cullin 3 (Cul3) requires that its target protein has a bric-a-brac/tram-track/broad-complex (BTB) domain to recognize it. Cul3 has been widely associated with Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1) and the cytoprotective nuclear factor erythroid 2 related factor 2 (Nrf2) pathway and the proper control of cell cycle progression...
June 2014: Cellular Signalling
#37
REVIEW
Shinichi Uchida, Eisei Sohara, Tatemitsu Rai, Sei Sasaki
In 2001, with-no-lysine (WNK) kinases were identified as the genes responsible for the human hereditary hypertensive disease pseudohypoaldosteronism type II (PHAII). It took a further 6 years to clarify that WNK kinases participate in a signaling cascade with oxidative stress-responsive gene 1 (OSR1), Ste20-related proline-alanine-rich kinase (SPAK), and thiazide-sensitive NaCl cotransporter (NCC) in the kidney and the constitutive activation of this signaling cascade is the molecular basis of PHAII. Since this discovery, the WNK-OSR1/SPAK-NCC signaling cascade has been shown to be involved not only in PHAII but also in the regulation of blood pressure under normal and pathogenic conditions, such as hyperinsulinemia...
February 2014: Biology of the Cell
#38
REVIEW
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
#39
JOURNAL ARTICLE
Kiyoshi Isobe, Takayasu Mori, Takako Asano, Hiroyuki Kawaguchi, Shigeaki Nonoyama, Naonori Kumagai, Fumiaki Kamada, Tetsuji Morimoto, Matsuhiko Hayashi, Eisei Sohara, Tatemitsu Rai, Sei Sasaki, Shinichi Uchida
The Na-Cl cotransporter (NCC) in the distal convoluted tubules in kidney is known to be excreted in urine. However, its clinical significance has not been established because of the lack of quantitative data on urinary NCC. We developed highly sensitive enzyme-linked immunosorbent assays (ELISAs) for urinary total NCC (tNCC) and its active form, phosphorylated NCC (pNCC). We first measured the excretion of tNCC and pT55-NCC in urinary exosomes in pseudohypoaldosteronism type II (PHAII) patients since PHAII is caused by NCC activation...
November 2013: American Journal of Physiology. Renal Physiology
#40
JOURNAL ARTICLE
Takayasu Mori, Eriko Kikuchi, Yuko Watanabe, Shinya Fujii, Mari Ishigami-Yuasa, Hiroyuki Kagechika, Eisei Sohara, Tatemitsu Rai, Sei Sasaki, Shinichi Uchida
WNKs (with-no-lysine kinases) are the causative genes of a hereditary hypertensive disease, PHAII (pseudohypoaldosteronism type II), and form a signal cascade with OSR1 (oxidative stress-responsive 1)/SPAK (STE20/SPS1-related proline/alanine-rich protein kinase) and Slc12a (solute carrier family 12) transporters. We have shown that this signal cascade regulates blood pressure by controlling vascular tone as well as renal NaCl excretion. Therefore agents that inhibit this signal cascade could be a new class of antihypertensive drugs...
November 1, 2013: Biochemical Journal
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