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Leping Shao, Li Cui, Jingru Lu, Yanhua Lang, Irene Bottillo, Xiangzhong Zhao
Pseudohypoaldosteronism type II (PHAII) is a rare renal tubular disease that is inherited in an autosomal dominant manner. Mutations in four genes ( WNK1 , WNK4 , CUL3, and KLHL3 ) have been identified to be responsible for this disease. Cullin 3 (CUL3) and KLHL3 are subunits of Cullin-RING E3 ubiquitin ligase complexes, and the serine-threonine kinases WNK1 and WNK4 are substrates of this ubiquitin ligase. For CUL3 , all mutations associated with PHAII exclusively lead to exon 9 skipping. In this study, we identified a Chinese PHAII kindred caused by a novel synonymous mutation (c...
March 2018: FEBS Open Bio
Gul Hassan Sethar, Aisha Almoghawi, Nargis Khan, Wehad Altourah, Najat Mohammed Ashour
Pseudohypoaldosteronism (PHA) type II is an extremely rare disorder which presents with hypertension, hyperkalemia, and normal anion gap metabolic acidosis. PHA II is also known as familial hyperkalemic hypertension, Gordon syndrome, and chloride shunt syndrome. PHA II is an autosomal dominant disorder and is caused by mutation in WNK1, WNK4, CULLIN3, KLHL3, OSR, SPAK gene. The expression of these proteins is limited to the distal convoluted tube and collecting duct of the kidney. PHA II usually responds to salt restriction and thiazide diuretics...
March 2018: Journal of the College of Physicians and Surgeons—Pakistan: JCPSP
Melaine A Kuenemann, Denis Fourches
The With-No-Lysine (WNK) serine/threonine kinase family constitutes a unique and distinctive branch of the kinome. The four proteins of this family (WNK1/2/3/4) are involved in blood pressure regulation, body fluid, and electrolyte homeostasis. Herein, we modeled and analyzed the binding modes of all publicly-available small orthosteric and allosteric binders (including WNK463 and WNK467) experimentally tested towards any of the WNK family member. To do so, we relied on state-of-the-art cheminformatics approaches including structure-based molecular docking and molecular dynamics simulations...
February 23, 2018: Molecular Informatics
Chloé Rafael, Christelle Soukaseum, Véronique Baudrie, Perrine Frère, Juliette Hadchouel
Mutations of the gene encoding WNK1 [With No lysine (K) kinase 1] or WNK4 cause Familial Hyperkalemic Hypertension (FHHt). Previous studies have shown that the activation of SPAK (Ste20-related Proline/Alanine-rich Kinase) plays a dominant role in the development of FHHt caused by WNK4 mutations. The implication of SPAK in FHHt caused by WNK1 mutation has never been investigated. To clarify this issue, we crossed WNK1+/FHHt mice with SPAK knock-in mice in which the T-loop Thr243 residue was mutated to alanine to prevent activation by WNK kinases...
February 19, 2018: Scientific Reports
Woo Young Chung, Jung Woo Han, Woon Heo, Min Goo Lee, Joo Young Kim
"With no lysine" (WNK) kinases have been shown to regulate various ion transporters in various tissues, but studies on the function of WNK kinases in the brain have been limited. In this study, we discovered that WNK1 and WNK4 in POMC-expressing neuronal cells in WNK1 overexpressed transgenic mice (WNK1 TG) decrease appetite via degradation of Kir6.2. Weight gain after 20 weeks of age was delayed in WNK1 TG mice as a result of reduced food intake. Expression of WNK1 and proopiomelanocortin (POMC) was higher in POMC-expressing neurons in the hypothalamus of WNK1 TG mice than in WT mice...
February 1, 2018: Molecular and Cellular Biochemistry
Cary R Boyd-Shiwarski, Daniel J Shiwarski, Ankita Roy, Lubika J Nkashama, Hima N Namboodiri, Jian Xie, Kara L McClain, Allison Marciszyn, Thomas R Kleyman, Roderick J Tan, Donna B Stolz, Manojkumar A Puthenveedu, Chou-Long Huang, Arohan R Subramanya
With-No-Lysine (WNK) kinases coordinate volume and potassium homeostasis by regulating renal tubular electrolyte transport. In the distal convoluted tubule (DCT), potassium imbalance causes WNK signaling complexes to concentrate into large discrete foci, which we call "WNK bodies." Though these structures have been reported previously, the mechanisms that drive their assembly remain obscure. Here, we show that kidney-specific WNK1 (KS-WNK1), a truncated kinase-defective WNK1 isoform that is highly expressed in the DCT, is critical for WNK body formation...
December 13, 2017: Molecular Biology of the Cell
Liang Ding, Lifang Zhang, Sudipta Biswas, Rebecca C Schugar, J Mark Brown, Tatiana Byzova, Eugene Podrez
Three Akt isoforms, encoded by 3 separate genes, are expressed in mammals. While the roles of Akt1 and Akt2 in metabolism are well established, it is not yet known whether Akt3 plays a role in metabolic diseases. We now report that Akt3 protects mice from high-fat diet-induced obesity by suppressing an alternative pathway of adipogenesis via with no lysine protein kinase-1 (WNK1) and serum/glucocorticoid-inducible kinase 1 (SGK1). We demonstrate that Akt3 specifically phosphorylates WNK1 at T58 and promotes its degradation via the ubiquitin-proteasome pathway...
November 16, 2017: JCI Insight
Adam Volanakis, Kinga Kamieniarz-Gdula, Margarita Schlackow, Nick J Proudfoot
Nuclear gene transcription is coordinated with transcript release from the chromatin template and messenger RNA (mRNA) export to the cytoplasm. Here we describe the role of nuclear-localized kinase WNK1 (with no lysine [K] 1) in the mammalian mRNA export pathway even though it was previously established as a critical regulator of ion homeostasis in the cytoplasm. Our data reveal that WNK1 phosphorylates the termination factor PCF11 on its RNA polymerase II (Pol II) C-terminal domain (CTD)-interacting domain (CID)...
November 1, 2017: Genes & Development
Martin Heubl, Jinwei Zhang, Jessica C Pressey, Sana Al Awabdh, Marianne Renner, Ferran Gomez-Castro, Imane Moutkine, Emmanuel Eugène, Marion Russeau, Kristopher T Kahle, Jean Christophe Poncer, Sabine Lévi
The K+ -Cl- co-transporter KCC2 (SLC12A5) tunes the efficacy of GABAA receptor-mediated transmission by regulating the intraneuronal chloride concentration [Cl- ]i . KCC2 undergoes activity-dependent regulation in both physiological and pathological conditions. The regulation of KCC2 by synaptic excitation is well documented; however, whether the transporter is regulated by synaptic inhibition is unknown. Here we report a mechanism of KCC2 regulation by GABAA receptor (GABAA R)-mediated transmission in mature hippocampal neurons...
November 24, 2017: Nature Communications
Michael Neidlin, Antonion Korcari, Giorgos Macheras, Leonidas G Alexopoulos
Articular cartilage is an avascular connective tissue responsible for bearing loads. Cell signaling plays a central role in cartilage homeostasis and tissue engineering by directing chondrocytes to synthesize/degrade the extracellular matrix or promote inflammatory responses. The aim of this paper was to investigate anabolic, catabolic and inflammatory pathways of well-known and underreported anabolic stimuli in 3D chondrocyte cultures and connect them to diverse cartilage responses including matrix regeneration and cell communication...
November 16, 2017: Annals of Biomedical Engineering
Viktor N Tomilin, Oleg Zaika, Arohan R Subramanya, Oleh Pochynyuk
The renal collecting duct contains two distinct cell types, principal and intercalated cells, expressing potassium Kir4.1/5.1 (KCNJ10/16) and chloride ClC-K2 (ClC-Kb in humans) channels on their basolateral membrane, respectively. Both channels are thought to play important roles in controlling systemic water-electrolyte balance and blood pressure. However, little is known about mechanisms regulating activity of Kir4.1/5.1 and ClC-K2/b. Here, we employed patch clamp analysis at the single channel and whole cell levels in freshly isolated mouse collecting ducts to investigate regulation of Kir4...
November 13, 2017: Pflügers Archiv: European Journal of Physiology
Vibhuti, Rehan Khan, Alpana Sharma, Suman Jain, Sujata Mohanty, Kameshwar Prasad
Stroke is a multi-factorial polygenic disease and is a major cause of death and adult disability. Administration of bone marrow stem cells protects ischemic rat brain by facilitating recovery of neurological functions. But the molecular mechanism of stem cells action and their effect on gene expression is not well explored. In this study, we have transplanted 1 × 106 human bone marrow mesenchymal stem cells (hBMMSCs) in middle cerebral artery occluded (MCAo) adult male Wistar rats through intracarotid artery route at 24 h after surgery...
December 2017: Journal of Neurochemistry
Yaya Zhou, Wei Sun, Ning Chen, Chen Xu, Xinxin Wang, Kun Dong, Binxue Zhang, Jian Zhang, Ning Hao, Aihua Sun, Handong Wei, Fuchu He, Ying Jiang
Metastasis is the essential cause for the high mortality of hepatocellular carcinoma (HCC). In order to investigate the mechanism of metastasis, and to discover therapeutic targets for HCC, the quantitative proteomic technique was applied to characterize the plasma membrane proteins of two HCC cell lines with low (MHCC97L) or high (MHCC97H) metastatic potentials. One of the plasma membrane proteins, sodium-potassium-chloride cotransporter 1 (NKCC1), was upregulated in MHCC97H cell line. Immunohistochemistry result in HCC patients showed that NKCC1 expression was associated with poor differentiation and microvascular invasion...
September 12, 2017: Oncotarget
Nyssa R Adams, Yasmin M Vasquez, Qianxing Mo, William Gibbons, Ertug Kovanci, Francesco J DeMayo
The differentiation of endometrial stromal cells into decidual cells, termed decidualization, is an integral step in the establishment of pregnancy. The mitogen-activated protein kinase homolog, WNK lysine deficient protein kinase 1 (WNK1), is activated downstream of epidermal growth factor receptor during decidualization. Primary human endometrial stromal cells (HESCs) were subjected to small interfering RNA knockdown of WNK1 followed by in vitro decidualization. This abrogated expression of the decidual marker genes, insulin like growth factor binding protein 1 (IGFBP1) and prolactin (PRL), and prevented adoption of decidual cell morphology...
September 1, 2017: Biology of Reproduction
Melissa K Frey, Fanny Dao, Narciso Olvera, Jason A Konner, Maura N Dickler, Douglas A Levine
OBJECTIVE: Bevacizumab, a monoclonal antibody to VEGF, has shown efficacy in ovarian, cervical and endometrial cancer in addition to several other solid tumors. Serious side effects include hypertension, proteinuria, bowel perforation, and thrombosis. We tested the hypothesis that genetic variation in hypertension-associated genes is associated with bevacizumab-induced hypertension (BIH). METHODS: Patients with solid tumors treated with bevacizumab in combination with other therapy were identified from six clinical trials...
December 2017: Gynecologic Oncology
Jen-Yu Hung, Meng-Chi Yen, Shu-Fang Jian, Cheng-Ying Wu, Wei-An Chang, Kuan-Ting Liu, Ya-Ling Hsu, Inn-Wen Chong, Po-Lin Kuo
The extracellular matrix is a component of physiological microenvironment and a regulator of cellular processes such as migration and proliferation. Secreted Protein Acidic and Rich in Cysteine (SPARC/osteonectin) is an extracellular matrix-associated glycoprotein involved in the regulation of cell proliferation and cell migration in several types of cancers. However, the role of SPARC in lung cancer is paradoxical and details of the regulatory mechanism are not well-known. In this study, we investigated novel SPARC-mediated signaling pathways...
September 8, 2017: Oncotarget
Rufeng Shi, Jiangbo Li, Jiyun He, Qingtao Meng, Zhiping Qian, Di Shi, Qi Liu, Yali Cai, Xinran Li, Xiaoping Chen
Tibetans have a higher essential hypertension prevalence compared with other ethnics in China. The reason might be due to their unique environmental influence, as well as genetic factor. However, limited studies focus on Tibetan genetics and its association with hypertension. The aim of this study was to investigate the association between With-No-Lysine (K) Kinase 1 (WNK1), Serine/Threonine kinase 39(STK39) genes variants and hypertension in the Tibetan population. 204 Tibetan hypertensive patients and 305 normotensive controls were recruited in an epidemiological survey conducted at 2 sites in the Ganzi Tibetan autonomous region...
September 25, 2017: Environmental and Molecular Mutagenesis
Kai Liu, Fang Qin, Xiaolu Sun, Yang Zhang, Jizheng Wang, Yajie Wu, Wenjun Ma, Wei Wang, Xueyi Wu, Ying Qin, Huimin Zhang, Xianliang Zhou, Haiying Wu, Rutai Hui, Yubao Zou, Xiongjing Jiang, Lei Song
BACKGROUND: The study aimed to analyze genes involved in Mendelian forms of low-renin hypertension in Chinese early-onset hypertensive patients. METHODS: A panel of nine genes, namely SCNN1B, SCNN1G, WNK1, WNK4, KLHL3, CUL3, nuclear receptor subfamily 3, group C (NR3C)1, NR3C2, and HSD11B2 were screened by targeted resequencing in 260 Chinese early-onset hypertensive patients. Additionally, exon 13 of both SCNN1B and SCNN1G was sequenced in an independent cohort of 506 Chinese early-onset hypertensive patients...
September 14, 2017: Journal of Hypertension
Lukas Klameth, Barbara Rath, Gerhard Hamilton
Gastric cancer exhibits a poor prognosis and is the third most common cause of cancer death worldwide. Chemotherapy of metastatic gastric cancer is based on combinations of platinum drugs and fluoropyrimidines, with added agents. Oxoplatin is a stable oral platinum(IV) prodrug which is converted to a highly active tetrachlorido(IV) complex under acidic conditions. In the present work, we studied the cytotoxic effects of oxoplatin against a panel of four gastric cancer cell lines in vitro. Furthermore, the role of HSP90 in chemoresistance of these lines was investigated using the specific inhibitor ganetespib...
2017: Journal of Cancer
Ken Yamada, Julian Levell, Taeyong Yoon, Darcy Kohls, David Yowe, Dean F Rigel, Hidetomo Imase, Jun Yuan, Kayo Yasoshima, Keith DiPetrillo, Lauren Monovich, Lingfei Xu, Meicheng Zhu, Mitsunori Kato, Monish Jain, Neeraja Idamakanti, Paul Taslimi, Toshio Kawanami, Upendra A Argikar, Vidya Kunjathoor, Xiaoling Xie, Yukiko I Yagi, Yuki Iwaki, Zachary Robinson, Hyi-Man Park
The observed structure-activity relationship of three distinct ATP noncompetitive With-No-Lysine (WNK) kinase inhibitor series, together with a crystal structure of a previously disclosed allosteric inhibitor bound to WNK1, led to an overlay hypothesis defining core and side-chain relationships across the different series. This in turn enabled an efficient optimization through scaffold morphing, resulting in compounds with a good balance of selectivity, cellular potency, and pharmacokinetic profile, which were suitable for in vivo proof-of-concept studies...
August 24, 2017: Journal of Medicinal Chemistry
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