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David Penton, Jan Czogalla, Agnieszka Wengi, Nina Himmerkus, Dominique Loffing-Cueni, Monique Carrel, Renuga Devi Rajaram, Olivier Staub, Markus Bleich, Frank Schweda, Johannes Loffing
A high dietary potassium (K(+) ) intake causes a rapid dephosphorylation, and hence inactivation, of the thiazide-sensitive NaCl cotransporter (NCC) in the renal distal convoluted tubule (DCT). Based on experiments in heterologous expression systems, it was proposed that changes in extracellular K(+) concentration ([K(+) ]ex ) modulate NCC phosphorylation via a Cl(-) dependent modulation of the WNK-SPAK/OSR1 kinase pathway. We used the isolated perfused mouse kidney technique and ex vivo preparations of mouse kidney slices to test the physiological relevance of this model on native DCT...
July 25, 2016: Journal of Physiology
Jingyue Xu, Han Liu, Ok Hee Chai, Yu Lan, Rulang Jiang
Renal hypoplasia is a common cause of pediatric renal failure and several adult-onset diseases. Recent studies have associated a variant of the OSR1 gene with reduction of newborn kidney size and function in heterozygotes and neonatal lethality with kidney defects in homozygotes. How OSR1 regulates kidney development and nephron endowment is not well understood, however. In this study, by using the recently developed CRISPR genome editing technology, we genetically labeled the endogenous Osr1 protein and show that Osr1 interacts with Wt1 in the developing kidney...
2016: PloS One
Eduardo R Argaiz, Gerardo Gamba
PURPOSE OF REVIEW: Abundant evidence supports that the NaCl cotransporter (NCC) activity is tightly regulated by the with-no-lysine (WNK) kinases. Here, we summarize the data regarding NCC regulation by WNKs, with a particular emphasis on WNK4. RECENT FINDINGS: Several studies involving in-vivo and in-vitro models have provided paradoxical data regarding WNK4 regulation of the NCC. Although some studies show that WNK4 can activate the NCC, other equally compelling studies show that WNK4 inhibits the NCC...
September 2016: Current Opinion in Nephrology and Hypertension
Jinrui Shi, Bruce J Drummond, Hongyu Wang, Rayeann L Archibald, Jeffrey E Habben
The phytohormone ethylene regulates plant growth and development as well as plant response to environmental cues. ARGOS genes reduce plant sensitivity to ethylene when overexpressed in transgenic Arabidopsis (Arabidopsis thaliana) and maize (Zea mays). A previous genetic study suggested that the endoplasmic reticulum and Golgi-localized maize ARGOS1 targets the ethylene signal transduction components at or upstream of CONSTITUTIVE TRIPLE RESPONSE1, but the mechanism of ARGOS modulating ethylene signaling is unknown...
August 2016: Plant Physiology
Xiangyu Zhou, Isao Naguro, Hidenori Ichijo, Kengo Watanabe
BACKGROUND: Osmotic stress arises from the difference between intracellular and extracellular osmolality. It induces cell swelling or shrinkage as a consequence of water influx or efflux, which threatens cellular activities. Mitogen-activated protein kinases (MAPKs) play central roles in signaling pathways in osmotic stress responses, including the regulation of intracellular levels of inorganic ions and organic osmolytes. SCOPE OF REVIEW: The present review summarizes the cellular osmotic stress response and the function and regulation of the vertebrate MAPK signaling pathways involved...
September 2016: Biochimica et Biophysica Acta
Artur Brandt, Katharina Löhers, Manfred Beier, Barbara Leube, Carmen de Torres, Jaume Mora, Parineeta Arora, Parmjit S Jat, Brigitte Royer-Pokora
We describe a stromal predominant Wilms tumor with focal anaplasia and a complex, tumor specific chromosome 11 aberration: a homozygous deletion of the entire WT1 gene within a heterozygous 11p13 deletion and an additional region of uniparental disomy (UPD) limited to 11p15.5-p15.2 including the IGF2 gene. The tumor carried a heterozygous p.T41A mutation in CTNNB1. Cells established from the tumor carried the same chromosome 11 aberration, but a different, homozygous p.S45Δ CTNNB1 mutation. Uniparental disomy (UPD) 3p21...
2016: PloS One
Rainelli Koumangoye, Eric Delpire
Proteomics studies have identified Ste20-related proline/alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1) in exosomes isolated from body fluids such as blood, saliva, and urine. Because proteomics studies likely overestimate the number of exosome proteins, we sought to confirm and extend this observation using traditional biochemical and cell biology methods. We utilized HEK293 cells in culture to verify the packaging of these Ste20 kinases in exosomes. Using a series of centrifugation and filtration steps of conditioned culture medium isolated from HEK293 cells, we isolated nanovesicles in the range of 40-100 nm...
July 1, 2016: American Journal of Physiology. Cell Physiology
Bernat Elvira, Yogesh Singh, Jamshed Warsi, Carlos Munoz, Florian Lang
BACKGROUND/AIMS: The oxidative stress-responsive kinase 1 (OSR1) and the serine/threonine kinases SPAK (SPS1-related proline/alanine-rich kinase) are under the control of WNK (with-no-K [Lys]) kinases. OSR1 and SPAK participate in diverse functions including cell volume regulation and neuronal excitability. Cell volume and neuronal excitation are further modified by the large conductance Ca2+-activated K+ channels (maxi K+ channel or BK channels). An influence of OSR1 and/or SPAK on BK channel activity has, however, never been shown...
2016: Cellular Physiology and Biochemistry
Kenichi Shukuya, Sayoko Ogura, Yasunori Tokuhara, Shigeo Okubo, Yutaka Yatomi, Minoru Tozuka, Tatsuo Shimosawa
BACKGROUND: Voided urine contains a variety of cells from the kidney and urinary tract and urinalysis provides us various information by investigating cellular components. We investigated urine sediment from renal impaired patients. RESULTS: We found 'round cell' to be distinct from known cells in sediment and is close to proximal convoluted tubule-derived cells based on morphology and molecular marker expression (GGT1 but not podocalyxin). Also it was positive for undifferentiated cell markers, including PAX2, WT1, OSR1, and SIX2...
June 1, 2016: Clinica Chimica Acta; International Journal of Clinical Chemistry
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
Mohammed Z Ferdaus, Karl W Barber, Karen I López-Cayuqueo, Andrew S Terker, Eduardo R Argaiz, Brandon M Gassaway, Régine Chambrey, Gerardo Gamba, Jesse Rinehart, James A McCormick
KEY POINTS: STE20 (Sterile 20)/SPS-1 related proline/alanine-rich kinase (SPAK) and oxidative stress-response kinase-1 (OSR1) phosphorylate and activate the renal Na(+) -K(+) -2Cl(-) cotransporter 2 (NKCC2) and Na(+) Cl(-) cotransporter (NCC). Mouse models suggest that OSR1 mainly activates NKCC2-mediated sodium transport along the thick ascending limb, while SPAK mainly activates NCC along the distal convoluted tubule, but the kinases may compensate for each other. We hypothesized that disruption of both kinases would lead to polyuria and severe salt-wasting, and generated SPAK/OSR1 double knockout mice to test this...
September 1, 2016: Journal of Physiology
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
Sergei V Kozlov, Ashley J Waardenberg, Kasper Engholm-Keller, Jonathan W Arthur, Mark E Graham, Martin Lavin
Ataxia-telangiectasia, mutated (ATM) protein plays a central role in phosphorylating a network of proteins in response to DNA damage. These proteins function in signaling pathways designed to maintain the stability of the genome and minimize the risk of disease by controlling cell cycle checkpoints, initiating DNA repair, and regulating gene expression. ATM kinase can be activated by a variety of stimuli, including oxidative stress. Here, we confirmed activation of cytoplasmic ATM by autophosphorylation at multiple sites...
March 2016: Molecular & Cellular Proteomics: MCP
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
Bernat Elvira, Jamshed Warsi, Myriam Fezai, Carlos Munoz, Florian Lang
BACKGROUND/AIMS: KCNQ1/E1 channels are expressed in diverse tissues and serve a variety of functions including endolymph secretion in the inner ear, cardiac repolarization, epithelial transport and cell volume regulation. Kinases involved in regulation of epithelial transport and cell volume include SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1), which are under control of WNK (with-no-K[Lys]) kinases. The present study explored whether KCNQ1/E1 channels are regulated by SPAK and/or OSR1...
2015: Cellular Physiology and Biochemistry
Myriam Fezai, Bernat Elvira, Jamshed Warsi, Mossadok Ben-Attia, Zohreh Hosseinzadeh, Florian Lang
BACKGROUND/AIMS: SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1), kinases controlled by WNK (with-no-K[Lys] kinase), are powerful regulators of cellular ion transport and blood pressure. Observations in gene-targeted mice disclosed an impact of SPAK/OSR1 on phosphate metabolism. The present study thus tested whether SPAK and/or OSR1 contributes to the regulation of the intestinal Na(+)-coupled phosphate co-transporter NaPi-IIb (SLC34A2)...
2015: Kidney & Blood Pressure Research
Zhongdi Huang, Liqun He, Di Huang, Shi Lei, Jiandong Gao
BACKGROUND: Chronic kidney disease poses a serious health problem worldwide with increasing prevalence and lack of effective treatment. This study aimed to investigate the mechanism of icariin in alleviating chronic renal failure induced by 5/6 nephrectomy in rats. METHODS: The chronic renal failure model was established by a two-phased 5/6 nephrectomy procedure. The model rats were given daily doses of water or icariin for 8 weeks. The kidney morphology was checked by HE staining...
2015: BMC Complementary and Alternative Medicine
Miho Watanabe, Atsuo Fukuda
γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter of the mature central nervous system (CNS). The developmental switch of GABAergic transmission from excitation to inhibition is induced by changes in Cl(-) gradients, which are generated by cation-Cl(-) co-transporters. An accumulation of Cl(-) by the Na(+)-K(+)-2Cl(-) co-transporter (NKCC1) increases the intracellular Cl(-) concentration ([Cl(-)]i) such that GABA depolarizes neuronal precursors and immature neurons. The subsequent ontogenetic switch, i...
2015: Frontiers in Cellular Neuroscience
Norihiro Kato, Marie Loh, Fumihiko Takeuchi, Niek Verweij, Xu Wang, Weihua Zhang, Tanika N Kelly, Danish Saleheen, Benjamin Lehne, Irene Mateo Leach, Alexander W Drong, James Abbott, Simone Wahl, Sian-Tsung Tan, William R Scott, Gianluca Campanella, Marc Chadeau-Hyam, Uzma Afzal, Tarunveer S Ahluwalia, Marc Jan Bonder, Peng Chen, Abbas Dehghan, Todd L Edwards, Tõnu Esko, Min Jin Go, Sarah E Harris, Jaana Hartiala, Silva Kasela, Anuradhani Kasturiratne, Chiea-Chuen Khor, Marcus E Kleber, Huaixing Li, Zuan Yu Mok, Masahiro Nakatochi, Nur Sabrina Sapari, Richa Saxena, Alexandre F R Stewart, Lisette Stolk, Yasuharu Tabara, Ai Ling Teh, Ying Wu, Jer-Yuarn Wu, Yi Zhang, Imke Aits, Alexessander Da Silva Couto Alves, Shikta Das, Rajkumar Dorajoo, Jemma C Hopewell, Yun Kyoung Kim, Robert W Koivula, Jian'an Luan, Leo-Pekka Lyytikäinen, Quang N Nguyen, Mark A Pereira, Iris Postmus, Olli T Raitakari, Molly Scannell Bryan, Robert A Scott, Rossella Sorice, Vinicius Tragante, Michela Traglia, Jon White, Ken Yamamoto, Yonghong Zhang, Linda S Adair, Alauddin Ahmed, Koichi Akiyama, Rasheed Asif, Tin Aung, Inês Barroso, Andrew Bjonnes, Timothy R Braun, Hui Cai, Li-Ching Chang, Chien-Hsiun Chen, Ching-Yu Cheng, Yap-Seng Chong, Rory Collins, Regina Courtney, Gail Davies, Graciela Delgado, Loi D Do, Pieter A Doevendans, Ron T Gansevoort, Yu-Tang Gao, Tanja B Grammer, Niels Grarup, Jagvir Grewal, Dongfeng Gu, Gurpreet S Wander, Anna-Liisa Hartikainen, Stanley L Hazen, Jing He, Chew-Kiat Heng, James E Hixson, Albert Hofman, Chris Hsu, Wei Huang, Lise L N Husemoen, Joo-Yeon Hwang, Sahoko Ichihara, Michiya Igase, Masato Isono, Johanne M Justesen, Tomohiro Katsuya, Muhammad G Kibriya, Young Jin Kim, Miyako Kishimoto, Woon-Puay Koh, Katsuhiko Kohara, Meena Kumari, Kenneth Kwek, Nanette R Lee, Jeannette Lee, Jiemin Liao, Wolfgang Lieb, David C M Liewald, Tatsuaki Matsubara, Yumi Matsushita, Thomas Meitinger, Evelin Mihailov, Lili Milani, Rebecca Mills, Nina Mononen, Martina Müller-Nurasyid, Toru Nabika, Eitaro Nakashima, Hong Kiat Ng, Kjell Nikus, Teresa Nutile, Takayoshi Ohkubo, Keizo Ohnaka, Sarah Parish, Lavinia Paternoster, Hao Peng, Annette Peters, Son T Pham, Mohitha J Pinidiyapathirage, Mahfuzar Rahman, Hiromi Rakugi, Olov Rolandsson, Michelle Ann Rozario, Daniela Ruggiero, Cinzia F Sala, Ralhan Sarju, Kazuro Shimokawa, Harold Snieder, Thomas Sparsø, Wilko Spiering, John M Starr, David J Stott, Daniel O Stram, Takao Sugiyama, Silke Szymczak, W H Wilson Tang, Lin Tong, Stella Trompet, Väinö Turjanmaa, Hirotsugu Ueshima, André G Uitterlinden, Satoshi Umemura, Marja Vaarasmaki, Rob M van Dam, Wiek H van Gilst, Dirk J van Veldhuisen, Jorma S Viikari, Melanie Waldenberger, Yiqin Wang, Aili Wang, Rory Wilson, Tien-Yin Wong, Yong-Bing Xiang, Shuhei Yamaguchi, Xingwang Ye, Robin D Young, Terri L Young, Jian-Min Yuan, Xueya Zhou, Folkert W Asselbergs, Marina Ciullo, Robert Clarke, Panos Deloukas, Andre Franke, Paul W Franks, Steve Franks, Yechiel Friedlander, Myron D Gross, Zhirong Guo, Torben Hansen, Marjo-Riitta Jarvelin, Torben Jørgensen, J Wouter Jukema, Mika Kähönen, Hiroshi Kajio, Mika Kivimaki, Jong-Young Lee, Terho Lehtimäki, Allan Linneberg, Tetsuro Miki, Oluf Pedersen, Nilesh J Samani, Thorkild I A Sørensen, Ryoichi Takayanagi, Daniela Toniolo, Habibul Ahsan, Hooman Allayee, Yuan-Tsong Chen, John Danesh, Ian J Deary, Oscar H Franco, Lude Franke, Bastiaan T Heijman, Joanna D Holbrook, Aaron Isaacs, Bong-Jo Kim, Xu Lin, Jianjun Liu, Winfried März, Andres Metspalu, Karen L Mohlke, Dharambir K Sanghera, Xiao-Ou Shu, Joyce B J van Meurs, Eranga Vithana, Ananda R Wickremasinghe, Cisca Wijmenga, Bruce H W Wolffenbuttel, Mitsuhiro Yokota, Wei Zheng, Dingliang Zhu, Paolo Vineis, Soterios A Kyrtopoulos, Jos C S Kleinjans, Mark I McCarthy, Richie Soong, Christian Gieger, James Scott, Yik-Ying Teo, Jiang He, Paul Elliott, E Shyong Tai, Pim van der Harst, Jaspal S Kooner, John C Chambers
We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure...
November 2015: Nature Genetics
Ankita Roy, Lama Al-Qusairi, Bridget F Donnelly, Caroline Ronzaud, Allison L Marciszyn, Fan Gong, Y P Christy Chang, Michael B Butterworth, Núria M Pastor-Soler, Kenneth R Hallows, Olivier Staub, Arohan R Subramanya
The thiazide-sensitive NaCl cotransporter (NCC) is important for renal salt handling and blood-pressure homeostasis. The canonical NCC-activating pathway consists of With-No-Lysine (WNK) kinases and their downstream effector kinases SPAK and OSR1, which phosphorylate NCC directly. The upstream mechanisms that connect physiological stimuli to this system remain obscure. Here, we have shown that aldosterone activates SPAK/OSR1 via WNK1. We identified 2 alternatively spliced exons embedded within a proline-rich region of WNK1 that contain PY motifs, which bind the E3 ubiquitin ligase NEDD4-2...
September 2015: Journal of Clinical Investigation
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