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https://www.readbyqxmd.com/read/28566208/development-of-wnk-signaling-inhibitors-as-a-new-class-of-antihypertensive-drugs
#1
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
https://www.readbyqxmd.com/read/28414128/impaired-degradation-of-medullary-wnk4-in-the-kidneys-of-klhl2-knockout-mice
#2
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
https://www.readbyqxmd.com/read/28391962/su9516-increases-%C3%AE-7%C3%AE-1-integrin-and-ameliorates-disease-progression-in-the-mdx-mouse-model-of-duchenne-muscular-dystrophy
#3
Apurva Sarathy, Ryan D Wuebbles, Tatiana M Fontelonga, Ashley R Tarchione, Lesley A Mathews Griner, Dante J Heredia, Andreia M Nunes, Suzann Duan, Paul D Brewer, Tyler Van Ry, Grant W Hennig, Thomas W Gould, Andrés E Dulcey, Amy Wang, Xin Xu, Catherine Z Chen, Xin Hu, Wei Zheng, Noel Southall, Marc Ferrer, Juan Marugan, Dean J Burkin
Duchenne muscular dystrophy (DMD) is a fatal muscle disease caused by mutations in the dystrophin gene, resulting in a complete loss of the dystrophin protein. Dystrophin is a critical component of the dystrophin glycoprotein complex (DGC), which links laminin in the extracellular matrix to the actin cytoskeleton within myofibers and provides resistance to shear stresses during muscle activity. Loss of dystrophin in DMD patients results in a fragile sarcolemma prone to contraction-induced muscle damage. The α7β1 integrin is a laminin receptor protein complex in skeletal and cardiac muscle and a major modifier of disease progression in DMD...
June 7, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28371477/rafoxanide-and-closantel-inhibit-spak-and-osr1-kinases-by-binding-to-a-highly-conserved-allosteric-site-on-their-c-terminal-domains
#4
Mubarak A AlAmri, Hachemi Kadri, Luke J Alderwick, Nigel S Simpkins, Youcef Mehellou
SPAK and OSR1 are two protein kinases that have emerged as attractive targets in the discovery of novel antihypertensive agents due to their role in regulating electrolyte balance in vivo. Herein we report the identification of an allosteric pocket on the highly conserved C-terminal domains of these two kinases, which influences their activity. We also show that some known WNK signaling inhibitors bind to this allosteric site. Using in silico screening, we identified the antiparasitic agent rafoxanide as a novel allosteric inhibitor of SPAK and OSR1...
March 31, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28341239/calcineurin-inhibitors-block-sodium-chloride-cotransporter-dephosphorylation-in-response-to%C3%A2-high-potassium-intake
#5
Wakana Shoda, Naohiro Nomura, Fumiaki Ando, Yutaro Mori, Takayasu Mori, Eisei Sohara, Tatemitsu Rai, Shinichi Uchida
Dietary potassium intake is inversely related to blood pressure and mortality. Moreover, the sodium-chloride cotransporter (NCC) plays an important role in blood pressure regulation and urinary potassium excretion in response to potassium intake. Previously, it was shown that NCC is activated by the WNK4-SPAK cascade and dephosphorylated by protein phosphatase. However, the mechanism of NCC regulation with acute potassium intake is still unclear. To identify the molecular mechanism of NCC regulation in response to potassium intake, we used adult C57BL/6 mice fed a 1...
February 2017: Kidney International
https://www.readbyqxmd.com/read/28282258/wnk1-is-an-unexpected-autophagy-inhibitor
#6
Sachith Gallolu Kankanamalage, A-Young Lee, Chonlarat Wichaidit, Andres Lorente-Rodriguez, Akansha M Shah, Steve Stippec, Angelique W Whitehurst, Melanie H Cobb
Autophagy is a cellular degradation pathway that is essential to maintain cellular physiology, and deregulation of autophagy leads to multiple diseases in humans. In a recent study, we discovered that the protein kinase WNK1 (WNK lysine deficient protein kinase 1) is an inhibitor of autophagy. The loss of WNK1 increases both basal and starvation-induced autophagy. In addition, the depletion of WNK1 increases the activation of the class III phosphatidylinositol 3-kinase (PtdIns3K) complex, which is required to induce autophagy...
May 4, 2017: Autophagy
https://www.readbyqxmd.com/read/28178566/wnk-kinase-signaling-in-ion-homeostasis-and-human-disease
#7
REVIEW
Masoud Shekarabi, Jinwei Zhang, Arjun R Khanna, David H Ellison, Eric Delpire, Kristopher T Kahle
WNK kinases, along with their upstream regulators (CUL3/KLHL3) and downstream targets (the SPAK/OSR1 kinases and the cation-Cl(-) cotransporters [CCCs]), comprise a signaling cascade essential for ion homeostasis in the kidney and nervous system. Recent work has furthered our understanding of the WNKs in epithelial transport, cell volume homeostasis, and GABA signaling, and uncovered novel roles for this pathway in immune cell function and cell proliferation.
February 7, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28096417/phosphorylation-by-pkc-and-pka-regulate-the-kinase-activity-and-downstream-signaling-of-wnk4
#8
Maria Castañeda-Bueno, Juan Pablo Arroyo, Junhui Zhang, Jeremy Puthumana, Orlando Yarborough, Shigeru Shibata, Lorena Rojas-Vega, Gerardo Gamba, Jesse Rinehart, Richard P Lifton
With-no-lysine kinase 4 (WNK4) regulates electrolyte homeostasis and blood pressure. WNK4 phosphorylates the kinases SPAK (Ste20-related proline alanine-rich kinase) and OSR1 (oxidative stress responsive kinase), which then phosphorylate and activate the renal Na-Cl cotransporter (NCC). WNK4 levels are regulated by binding to Kelch-like 3, targeting WNK4 for ubiquitylation and degradation. Phosphorylation of Kelch-like 3 by PKC or PKA downstream of AngII or vasopressin signaling, respectively, abrogates binding...
January 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28004876/towards-the-development-of-small-molecule-mo25-binders-as-potential-indirect-spak-osr1-kinase-inhibitors
#9
Hachemi Kadri, Mubarak A Alamri, Iva H Navratilova, Luke J Alderwick, Nigel S Simpkins, Youcef Mehellou
The binding of the scaffolding protein MO25 to SPAK and OSR1 protein kinases, which regulate ion homeostasis, causes increases of up to 100-fold in their catalytic activity. Various animal models have shown that the inhibition of SPAK and OSR1 lowers blood pressure, and so here we present a new indirect approach to inhibiting SPAK and OSR1 kinases by targeting their protein partner MO25. To explore this approach, we developed a fluorescent polarisation assay and used it in screening of a small in-house library of ≈4000 compounds...
December 22, 2016: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28003191/calcineurin-inhibitor-cyclosporine-a-activates-renal-na-k-cl-cotransporters-via-local-and-systemic-mechanisms
#10
K I Blankenstein, A Borschewski, R Labes, A Paliege, C Boldt, J A McCormick, D H Ellison, M Bader, S Bachmann, K Mutig
Calcineurin dephosphorylates nuclear factor of activated T cells transcription factors, thereby facilitating T cell-mediated immune responses. Calcineurin inhibitors are instrumental for immunosuppression after organ transplantation but may cause side effects, including hypertension and electrolyte disorders. Kidneys were recently shown to display activation of the furosemide-sensitive Na-K-2Cl cotransporter (NKCC2) of the thick ascending limb and the thiazide-sensitive Na-Cl cotransporter (NCC) of the distal convoluted tubule upon calcineurin inhibition using cyclosporin A (CsA)...
March 1, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/27983989/potassium-depletion-stimulates-na-cl-cotransporter-via-phosphorylation-and-inactivation-of-the-ubiquitin-ligase-kelch-like-3
#11
Kenichi Ishizawa, Ning Xu, Johannes Loffing, Richard P Lifton, Toshiro Fujita, Shunya Uchida, Shigeru Shibata
Kelch-like 3 (KLHL3) is a component of an E3 ubiquitin ligase complex that regulates blood pressure by targeting With-No-Lysine (WNK) kinases for degradation. Mutations in KLHL3 cause constitutively increased renal salt reabsorption and impaired K(+) secretion, resulting in hypertension and hyperkalemia. Although clinical studies have shown that dietary K(+) intake affects blood pressure, the mechanisms have been obscure. In this study, we demonstrate that the KLHL3 ubiquitin ligase complex is involved in the low-K(+)-mediated activation of Na-Cl cotransporter (NCC) in the kidney...
October 28, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27942049/potassium-depletion-stimulates-na-cl-cotransporter-via-phosphorylation-and-inactivation-of-the-ubiquitin-ligase-kelch-like-3
#12
Kenichi Ishizawa, Ning Xu, Johannes Loffing, Richard P Lifton, Toshiro Fujita, Shunya Uchida, Shigeru Shibata
Kelch-like 3 (KLHL3) is a component of an E3 ubiquitin ligase complex that regulates blood pressure by targeting With-No-Lysine (WNK) kinases for degradation. Mutations in KLHL3 cause constitutively increased renal salt reabsorption and impaired K(+) secretion, resulting in hypertension and hyperkalemia. Although clinical studies have shown that dietary K(+) intake affects blood pressure, the mechanisms have been obscure. In this study, we demonstrate that the KLHL3 ubiquitin ligase complex is involved in the low-K(+)-mediated activation of Na-Cl cotransporter (NCC) in the kidney...
November 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27853306/osr1-and-spak-cooperatively-modulate-sertoli-cell-support-of-mouse-spermatogenesis
#13
Yung-Liang Liu, Sung-Sen Yang, Shyi-Jou Chen, Yu-Chun Lin, Chin-Chen Chu, Hsin-Hui Huang, Fung-Wei Chang, Mu-Hsien Yu, Shih-Hua Lin, Gwo-Jang Wu, Huey-Kang Sytwu
We investigated the role of oxidative stress-responsive kinase-1 (OSR1) and STE20 (sterile 20)/SPS1-related proline/alanine-rich kinase (SPAK), upstream regulators of the Na(+)-K(+)-2Cl(-) cotransporter (NKCC1)-essential for spermatogenesis-in mouse models of male fertility. Global OSR1(+/-) gene mutations, but not global SPAK(-/-) or Sertoli cell (SC)-specific OSR1 gene knockout (SC-OSR1(-/-)), cause subfertility with impaired sperm function and are associated with reduced abundance of phosphorylated (p)-NKCC1 but increased p-SPAK expression in testicular tissue and spermatozoa...
November 17, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27457700/extracellular-k-rapidly-controls-nacl-cotransporter-phosphorylation-in-the-native-distal-convoluted-tubule-by-cl-dependent-and-independent-mechanisms
#14
David Penton, Jan Czogalla, Agnieszka Wengi, Nina Himmerkus, Dominique Loffing-Cueni, Monique Carrel, Renuga Devi Rajaram, Olivier Staub, Markus Bleich, Frank Schweda, Johannes Loffing
KEY POINTS: High dietary potassium (K(+) ) intake dephosphorylates and inactivates the NaCl cotransporter (NCC) in the renal distal convoluted tubule (DCT). Using several ex vivo models, we show that physiological changes in extracellular K(+) , similar to those occurring after a K(+) rich diet, are sufficient to promote a very rapid dephosphorylation of NCC in native DCT cells. Although the increase of NCC phosphorylation upon decreased extracellular K(+) appears to depend on cellular Cl(-) fluxes, the rapid NCC dephosphorylation in response to increased extracellular K(+) is not Cl(-) -dependent...
November 1, 2016: Journal of Physiology
https://www.readbyqxmd.com/read/27322883/the-regulation-of-na-cl-cotransporter-by-with-no-lysine-kinase-4
#15
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
https://www.readbyqxmd.com/read/27261090/mitogen-activated-protein-kinases-as-key-players-in-osmotic-stress-signaling
#16
REVIEW
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
https://www.readbyqxmd.com/read/27122160/the-ste20-kinases-spak-and-osr1-travel-between-cells-through-exosomes
#17
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
https://www.readbyqxmd.com/read/27119824/osr1-and-spak-sensitivity-of-large-conductance-ca2-activated-k-channel
#18
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
https://www.readbyqxmd.com/read/27076645/the-cul3-klhl3-wnk-spak-osr1-pathway-as-a-target-for-antihypertensive-therapy
#19
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
https://www.readbyqxmd.com/read/27068441/spak-and-osr1-play-essential-roles-in-potassium-homeostasis-through-actions-on-the-distal-convoluted-tubule
#20
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
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