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https://www.readbyqxmd.com/read/28414128/impaired-degradation-of-medullary-wnk4-in-the-kidneys-of-klhl2-knockout-mice
#1
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)...
April 13, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28389565/akt3-kinase-suppresses-pinocytosis-of-low-density-lipoprotein-by-macrophages-via-novel-wnk-sgk1-cdc42-pathway
#2
Liang Ding, Lifang Zhang, Michael Kim, Tatiana Byzova, Eugene Podrez
Fluid-phase pinocytosis of Low-density lipoprotein (LDL) by macrophages is regarded as a novel promising target to reduce macrophage cholesterol accumulation in atherosclerotic lesions. The mechanisms of regulation of fluid-phase pinocytosis in macrophages and specifically the role of Akt kinases are poorly understood. We have previously found that increased lipoprotein uptake via the receptor independent process in Akt3 kinase deficient macrophages contributes to increased atherosclerosis in Akt3-/- mice. The mechanism by which Akt3 deficiency promotes lipoprotein uptake in macrophages is unknown...
April 7, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28365586/enac-and-romk-activity-are-inhibited-in-the-dct2-cnt-of-tgwnk4-phaii-mice
#3
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) (TgWnk4(PHAII)) 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
https://www.readbyqxmd.com/read/28314693/wnk4-is-an-adipogenic-factor-and-its-deletion-reduces-diet-induced-obesity-in-mice
#4
Daiei Takahashi, Takayasu Mori, Eisei Sohara, Miyako Tanaka, Motoko Chiga, Yuichi Inoue, Naohiro Nomura, Moko Zeniya, Hiroki Ochi, Shu Takeda, Takayoshi Suganami, Tatemitsu Rai, Shinichi Uchida
The with-no-lysine kinase (WNK) 4 gene is a causative gene in pseudohypoaldosteronism type II. Although WNKs are widely expressed in the body, neither their metabolic functions nor their extrarenal role is clear. In this study, we found that WNK4 was expressed in mouse adipose tissue and 3T3-L1 adipocytes. In mouse primary preadipocytes and in 3T3-L1 adipocytes, WNK4 was markedly induced in the early phase of adipocyte differentiation. WNK4 expression preceded the expression of key transcriptional factors PPARγ and C/EBPα...
March 8, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28289184/renal-tubular-ubiquitin-protein-ligase-nedd4-2-is-required-for-renal-adaptation-during-long-term-potassium-depletion
#5
Lama Al-Qusairi, Denis Basquin, Ankita Roy, Renuga Devi Rajaram, Marc P Maillard, Arohan R Subramanya, Olivier Staub
Adaptation of the organism to potassium (K(+)) deficiency requires precise coordination among organs involved in K(+) homeostasis, including muscle, liver, and kidney. How the latter performs functional and molecular changes to ensure K(+) retention is not well understood. Here, we investigated the role of ubiquitin-protein ligase NEDD4-2, which negatively regulates the epithelial sodium channel (ENaC), Na(+)/Cl(-) cotransporter (NCC), and with no-lysine-kinase 1 (WNK1). After dietary K(+) restriction for 2 weeks, compared with control littermates, inducible renal tubular NEDD4-2 knockout (Nedd4L(Pax8/LC1) ) mice exhibited severe hypokalemia and urinary K(+) wasting...
March 13, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28237360/involvement-of-wnk1-mediated-potassium-channels-in-the-sexual-dimorphism-of-blood-pressure
#6
Guofeng Yu, Mengting Cheng, Wei Wang, Rong Zhao, Zhen Liu
Potassium homeostasis plays an essential role in the control of blood pressure. It is unknown, however, whether potassium balance is involved in the gender-associated blood pressure differences. We therefore investigated the possible mechanism of sexual dimorphism in blood pressure regulation by measuring the blood pressure, plasma potassium, renal actions of potassium channels and upstream regulator in male and female mice. Here we found that female mice exhibited lower blood pressure and higher plasma K(+) level as compared to male littermates...
April 1, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28236964/wnk-kinases-in-development-and-disease
#7
Aylin R Rodan, Andreas Jenny
WNK (With-No-Lysine (K)) kinases are serine-threonine kinases characterized by an atypical placement of a catalytic lysine within the kinase domain. Mutations in human WNK1 or WNK4 cause an autosomal dominant syndrome of hypertension and hyperkalemia, reflecting the fact that WNK kinases are critical regulators of renal ion transport processes. Here, the role of WNKs in the regulation of ion transport processes in vertebrate and invertebrate renal function, cellular and organismal osmoregulation, and cell migration and cerebral edema will be reviewed, along with emerging literature demonstrating roles for WNKs in cardiovascular and neural development, Wnt signaling, and cancer...
2017: Current Topics in Developmental Biology
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/28052936/klhl3-knockout-mice-reveal-the-physiological-role-of-klhl3-and-the-pathophysiology-of-pseudohypoaldosteronism-type-ii-caused-by-mutant-klhl3
#9
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
https://www.readbyqxmd.com/read/27983989/potassium-depletion-stimulates-na-cl-cotransporter-via-phosphorylation-and-inactivation-of-the-ubiquitin-ligase-kelch-like-3
#10
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
#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...
November 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27911840/multistep-regulation-of-autophagy-by-wnk1
#12
Sachith Gallolu Kankanamalage, A-Young Lee, Chonlarat Wichaidit, Andres Lorente-Rodriguez, Akansha M Shah, Steve Stippec, Angelique W Whitehurst, Melanie H Cobb
The with-no-lysine (K) (WNK) kinases are an atypical family of protein kinases that regulate ion transport across cell membranes. Mutations that result in their overexpression cause hypertension-related disorders in humans. Of the four mammalian WNKs, only WNK1 is expressed throughout the body. We report that WNK1 inhibits autophagy, an intracellular degradation pathway implicated in several human diseases. Using small-interfering RNA-mediated WNK1 knockdown, we show autophagosome formation and autophagic flux are accelerated...
December 13, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27811182/leveraging-unique-structural-characteristics-of-wnk-kinases-to-achieve-therapeutic-inhibition
#13
REVIEW
Jinwei Zhang, Xianming Deng, Kristopher T Kahle
The with-no-lysine (K) WNK kinases are master regulators of the Na(+)-(K(+))-Cl(-) cotransporters, including the renal-specific NCC and NKCC2 cotransporters. The discovery of WNK463, an orally bioavailable pan-WNK kinase inhibitor that exploits unique structural properties of the WNK catalytic domain to achieve high affinity and kinase selectivity, illustrates a strategy of leveraging distinct kinase features to develop specific inhibitors and validates the genetic predictions of the in vivo pharmacology of WNK inhibition...
October 18, 2016: Science Signaling
https://www.readbyqxmd.com/read/27798271/wnk-cab39-nkcc1-signaling-increases-the-susceptibility-to-ischemic-brain-damage-in-hypertensive-rats
#14
Mohammad Iqbal H Bhuiyan, Shanshan Song, Hui Yuan, Gulnaz Begum, Julia Kofler, Kristopher T Kahle, Sung-Sen Yang, Shih-Hua Lin, Seth L Alper, Arohan R Subramanya, Dandan Sun
With-no-lysine kinase (WNK) and Na(+)-K(+)-2Cl(-) cotransporter 1 (NKCC1) are involved in the pathogenesis of hypertension. In this study, we investigated the WNK-NKCC1 signaling pathway in spontaneously hypertensive rats (SHR) and their associated susceptibility to stroke injury. Basal NKCC1 protein levels were higher in SHR than in normotensive Wistar Kyoto (WKY) rat brains. After inducing ischemic stroke, adult male WKY and SHR received either saline or NKCC1 inhibitor bumetanide (10 mg/kg/day, i.p.) starting at 3-h post-reperfusion...
January 1, 2016: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/27753931/os-05-06-in-primary-aldosteronism-mineralocorticoids-and-potassium-influence-abundance-of-the-thiazide-sensitive-sodium-chloride-cotransporter
#15
Wolley Mj, Wu A, Xu S, Gordon Rd, Fenton Ra, Stowasser M
BACKGROUND: Distal tubular sodium retention is a potent driver of hypertension, with the thiazide sensitive sodium-chloride cotransporter (NCC) a key player. The upstream modulators of NCC are unclear, but recent evidence has revealed the kinases 'with-no-lysine kinase 4' (WNK4) and 'STE20/SPS1-related, proline alanine-rich kinase' (SPAK) to be involved. The wider role of mineralocorticoids is poorly understood, but animal models implicate aldosterone as a potent regulator, possibly via effects on plasma potassium...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27712055/discovery-and-characterization-of-allosteric-wnk-kinase-inhibitors
#16
Ken Yamada, Ji-Hu Zhang, Xiaoling Xie, Juergen Reinhardt, Amy Qiongshu Xie, Daniel LaSala, Darcy Kohls, David Yowe, Debra Burdick, Hajime Yoshisue, Hiromichi Wakai, Isabel Schmidt, Jason Gunawan, Kayo Yasoshima, Q Kimberley Yue, Mitsunori Kato, Muneto Mogi, Neeraja Idamakanti, Natasha Kreder, Peter Drueckes, Pramod Pandey, Toshio Kawanami, Waanjeng Huang, Yukiko I Yagi, Zhan Deng, Hyi-Man Park
Protein kinases are known for their highly conserved adenosine triphosphate (ATP)-binding site, rendering the discovery of selective inhibitors a major challenge. In theory, allosteric inhibitors can achieve high selectivity by targeting less conserved regions of the kinases, often with an added benefit of retaining efficacy under high physiological ATP concentration. Although often overlooked in favor of ATP-site directed approaches, performing a screen at high ATP concentration or stringent hit triaging with high ATP concentration offers conceptually simple methods of identifying inhibitors that bind outside the ATP pocket...
December 16, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27643324/os-05-06-in-primary-aldosteronism-mineralocorticoids-and-potassium-influence-abundance-of-the-thiazide-sensitive-sodium-chloride-cotransporter
#17
Wolley Mj, Wu A, Xu S, Gordon Rd, Fenton Ra, Stowasser M
BACKGROUND: Distal tubular sodium retention is a potent driver of hypertension, with the thiazide sensitive sodium-chloride cotransporter (NCC) a key player. The upstream modulators of NCC are unclear, but recent evidence has revealed the kinases 'with-no-lysine kinase 4' (WNK4) and 'STE20/SPS1-related, proline alanine-rich kinase' (SPAK) to be involved. The wider role of mineralocorticoids is poorly understood, but animal models implicate aldosterone as a potent regulator, possibly via effects on plasma potassium...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27622885/fgf23-klotho-signaling-axis-in-the-kidney
#18
REVIEW
Reinhold G Erben, Olena Andrukhova
Fibroblast growth factor-23 (FGF23) is a bone-derived hormone protecting against the potentially deleterious effects of hyperphosphatemia by suppression of phosphate reabsorption and of active vitamin D hormone synthesis in the kidney. The kidney is one of the main target organs of FGF23 signaling. The purpose of this review is to highlight the recent advances in the area of FGF23-Klotho signaling in the kidney. During recent years, it has become clear that FGF23 acts independently on proximal and distal tubular epithelium...
September 10, 2016: Bone
https://www.readbyqxmd.com/read/27595330/small-molecule-wnk-inhibition-regulates-cardiovascular-and-renal-function
#19
Ken Yamada, Hyi-Man Park, Dean F Rigel, Keith DiPetrillo, Erin J Whalen, Anthony Anisowicz, Michael Beil, James Berstler, Cara Emily Brocklehurst, Debra A Burdick, Shari L Caplan, Michael P Capparelli, Guanjing Chen, Wei Chen, Bethany Dale, Lin Deng, Fumin Fu, Norio Hamamatsu, Kouki Harasaki, Tracey Herr, Peter Hoffmann, Qi-Ying Hu, Waan-Jeng Huang, Neeraja Idamakanti, Hidetomo Imase, Yuki Iwaki, Monish Jain, Jey Jeyaseelan, Mitsunori Kato, Virendar K Kaushik, Darcy Kohls, Vidya Kunjathoor, Daniel LaSala, Jongchan Lee, Jing Liu, Yang Luo, Fupeng Ma, Ruowei Mo, Sarah Mowbray, Muneto Mogi, Flavio Ossola, Pramod Pandey, Sejal J Patel, Swetha Raghavan, Bahaa Salem, Yuka H Shanado, Gary M Trakshel, Gordon Turner, Hiromichi Wakai, Chunhua Wang, Stephen Weldon, Jennifer B Wielicki, Xiaoling Xie, Lingfei Xu, Yukiko I Yagi, Kayo Yasoshima, Jianning Yin, David Yowe, Ji-Hu Zhang, Gang Zheng, Lauren Monovich
The With-No-Lysine (K) (WNK) kinases play a critical role in blood pressure regulation and body fluid and electrolyte homeostasis. Herein, we introduce the first orally bioavailable pan-WNK-kinase inhibitor, WNK463, that exploits unique structural features of the WNK kinases for both affinity and kinase selectivity. In rodent models of hypertension, WNK463 affects blood pressure and body fluid and electro-lyte homeostasis, consistent with WNK-kinase-associated physiology and pathophysiology.
November 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27322883/the-regulation-of-na-cl-cotransporter-by-with-no-lysine-kinase-4
#20
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
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