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https://www.readbyqxmd.com/read/29602832/intracellular-chloride-and-scaffold-protein-mo25-cooperatively-regulate-transepithelial-ion-transport-through-wnk-signaling-in-the-malpighian-tubule
#1
Qifei Sun, Yipin Wu, Sima Jonusaite, John M Pleinis, John M Humphreys, Haixia He, Jeffrey N Schellinger, Radha Akella, Drew Stenesen, Helmut Krämer, Elizabeth J Goldsmith, Aylin R Rodan
Background With No Lysine kinase (WNK) signaling regulates mammalian renal epithelial ion transport to maintain electrolyte and BP homeostasis. Our previous studies showed a conserved role for WNK in the regulation of transepithelial ion transport in the Drosophila Malpighian tubule. Methods Using in vitro assays and transgenic Drosophila lines, we examined two potential WNK regulators, chloride ion and the scaffold protein mouse protein 25 (Mo25), in the stimulation of transepithelial ion flux. Results In vitro , autophosphorylation of purified Drosophila WNK decreased as chloride concentration increased...
March 30, 2018: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/29596900/role-of-nitric-oxide-and-wnk-spak-osr1-kcc2-signaling-in-daily-changes-in-gabaergic-inhibition-in-the-rat-dorsal-raphe-neurons
#2
Mi Jung Kim, Hye Jin Yang, Younghoon Kim, Insug Kang, Sung Soo Kim, Young-Wuk Cho
Serotonergic neurons in the dorsal raphe nucleus (DRN) act as wake-inducing neurons in the sleep-wake cycle and are controlled by gamma-aminobutyric acid (GABA) synaptic inputs. We investigated daily changes in GABAergic inhibition of the rat DRN neurons and the role of nitric oxide (NO) and cation-chloride co-transporters in the GABAergic action. Neuronal NO synthase (nNOS) was co-expressed in 74% of serotonergic DRN neurons and nNOS expression was higher during daytime (the sleep cycle) than that during nighttime (the wake cycle)...
March 27, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29581290/osr1-regulates-a-subset-of-inward-rectifier-potassium-channels-via-a-binding-motif-variant
#3
Clinton A Taylor, Sung-Wan An, Sachith Gallolu Kankanamalage, Steve Stippec, Svetlana Earnest, Ashesh T Trivedi, Jonathan Zijiang Yang, Hamid Mirzaei, Chou-Long Huang, Melanie H Cobb
The with-no-lysine (K) (WNK) signaling pathway to STE20/SPS1-related proline- and alanine-rich kinase (SPAK) and oxidative stress-responsive 1 (OSR1) kinase is an important mediator of cell volume and ion transport. SPAK and OSR1 associate with upstream kinases WNK 1-4, substrates, and other proteins through their C-terminal domains which interact with linear R-F-x-V/I sequence motifs. In this study we find that SPAK and OSR1 also interact with similar affinity with a motif variant, R-x-F-x-V/I. Eight of 16 human inward rectifier K+ channels have an R-x-F-x-V motif...
April 10, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29511024/genome-wide-strategies-identify-downstream-target-genes-of-connective-tissue-associated-transcription-factors
#4
Mickael Orgeur, Marvin Martens, Georgeta Leonte, Sonya Nassari, Marie-Ange Bonnin, Stefan T Börno, Bernd Timmermann, Jochen Hecht, Delphine Duprez, Sigmar Stricker
Connective tissues support organs and play crucial roles in development, homeostasis and fibrosis, yet our understanding of their formation is still limited. To gain insight into the molecular mechanisms of connective tissue specification, we selected five zinc finger transcription factors - OSR1, OSR2, EGR1, KLF2 and KLF4 - based on their expression patterns and/or known involvement in connective tissue subtype differentiation. RNA-seq and ChIP-seq profiling revealed a set of common genes regulated by all five transcription factors, which we propose as connective tissue core expression set...
March 6, 2018: Development
https://www.readbyqxmd.com/read/29510178/metformin-increases-urinary-sodium-excretion-by-reducing-phosphorylation-of-the-sodium-chloride-cotransporter
#5
Hiroko Hashimoto, Naohiro Nomura, Wakana Shoda, Kiyoshi Isobe, Hiroaki Kikuchi, Kouhei Yamamoto, Takuya Fujimaru, Fumiaki Ando, Takayasu Mori, Tomokazu Okado, Tatemitsu Rai, Shinichi Uchida, Eisei Sohara
OBJECTIVE: Metformin is an antidiabetic drug that is widely used to treat patients with diabetes mellitus. Recent studies have reported that treatment with metformin not only improved blood glucose levels but also reduced blood pressure. However, it remains unclear how metformin reduces blood pressure. We hypothesized that metformin affects sodium reabsorption in the kidneys. METHODS: Urinary sodium excretion and expression of renal sodium transporters were examined in 8-week-old male C57BL/6 mice with acute and chronic treatment of metformin...
March 3, 2018: Metabolism: Clinical and Experimental
https://www.readbyqxmd.com/read/29377931/transcriptional-regulatory-control-of-mammalian-nephron-progenitors-revealed-by-multi-factor-cistromic-analysis-and-genetic-studies
#6
Lori L O'Brien, Qiuyu Guo, Emad Bahrami-Samani, Joo-Seop Park, Sean M Hasso, Young-Jin Lee, Alan Fang, Albert D Kim, Jinjin Guo, Trudy M Hong, Kevin A Peterson, Scott Lozanoff, Ramya Raviram, Bing Ren, Ben Fogelgren, Andrew D Smith, Anton Valouev, Andrew P McMahon
Nephron progenitor number determines nephron endowment; a reduced nephron count is linked to the onset of kidney disease. Several transcriptional regulators including Six2, Wt1, Osr1, Sall1, Eya1, Pax2, and Hox11 paralogues are required for specification and/or maintenance of nephron progenitors. However, little is known about the regulatory intersection of these players. Here, we have mapped nephron progenitor-specific transcriptional networks of Six2, Hoxd11, Osr1, and Wt1. We identified 373 multi-factor associated 'regulatory hotspots' around genes closely associated with progenitor programs...
January 29, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29361671/mechanisms-and-controversies-in-mutant-cul3-mediated-familial-hyperkalemic-hypertension
#7
Mohammed Zubaerul Ferdaus, James A McCormick
Autosomal dominant mutations in Cullin3 (Cul3) cause the most severe form of Familial Hyperkalemic Hypertension (FHHt). Cul3 mutations cause skipping of exon 9 which results in an internal deletion of 57 amino acids from the CUL3 protein (CUL3-∆9). The precise mechanism by which this altered form of CUL3 causes FHHt is controversial. CUL3 is a member of the Cullin-Ring ubiquitin Ligase (CRL) family which mediates ubiquitination and thus degradation of cellular proteins including With-no-lysine [K] kinases (WNKs)...
January 17, 2018: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/29234951/zinc-finger-transcription-factor-odd-skipped-related-1-regulates-cranial-bone-formation
#8
Shinji Kawai, Masashi Yamauchi, Atsuo Amano
Knowledge of the molecular mechanisms of bone formation has been advanced by novel findings related to genetic control. Odd-skipped related 1 (Osr1) is known to play important roles in embryonic, heart, and urogenital development. To elucidate the in vivo function of Osr1 in bone formation, we generated transgenic mice overexpressing full-length Osr1 under control of its 2.8-kb promoter, which were smaller than their wild-type littermates. Notably, abnormalities in the skull of Osr1 transgenic mice were revealed by analysis of X-ray, skeletal preparation, and morphological findings, including round skull and cranial dysraphism...
December 12, 2017: Journal of Bone and Mineral Metabolism
https://www.readbyqxmd.com/read/29222527/the-chemokines-cxcl12-and-cxcl14-differentially-regulate-connective-tissue-markers-during-limb-development
#9
Sonya Nassari, Cédrine Blavet, Marie-Ange Bonnin, Sigmar Stricker, Delphine Duprez, Claire Fournier-Thibault
Connective tissues (CT) support and connect organs together. Understanding the formation of CT is important, as CT deregulation leads to fibrosis. The identification of CT specific markers has contributed to a better understanding of CT function during development. In developing limbs, Osr1 transcription factor is involved in the differentiation of irregular CT while the transcription factor Scx labels tendon. In this study, we show that the CXCL12 and CXCL14 chemokines display distinct expression pattern in limb CT during chick development...
December 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29123220/significance-of-dopamine-d-1-receptor-signalling-for-steroidogenic-differentiation-of-human-induced-pluripotent-stem-cells
#10
Koji Matsuo, Masakatsu Sone, Kyoko Honda-Kohmo, Takafumi Toyohara, Takuhiro Sonoyama, Daisuke Taura, Katsutoshi Kojima, Yorihide Fukuda, Youichi Ohno, Mayumi Inoue, Akira Ohta, Kenji Osafune, Kazuwa Nakao, Nobuya Inagaki
Human induced pluripotent stem cells (hiPSCs) are expected to be both a revolutionary cell source for regenerative medicine and a powerful tool to investigate the molecular mechanisms underlying human cell development in vitro. In the present study, we tried to elucidate the steroidogenic differentiation processes using hiPSC-derived intermediate mesoderm (IM) that is known to be the origin of the human adrenal cortex and gonads. We first performed chemical screening to identify small molecules that induce steroidogenic differentiation of IM cells expressing Odd-skipped related 1 (OSR1), an early IM marker...
November 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29029515/discovery-of-nkcc1-as-a-potential-therapeutic-target-to-inhibit-hepatocellular-carcinoma-cell-growth-and-metastasis
#11
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
https://www.readbyqxmd.com/read/28938435/the-role-of-sequential-bmp-signaling-in-directing-human-embryonic-stem-cells-to-bipotential-gonadal-cells
#12
Kirsi Sepponen, Karolina Lundin, Katri Knuus, Pia Väyrynen, Taneli Raivio, Juha S Tapanainen, Timo Tuuri
Context: Human gonads arise as a pair of epithelial ridges on the surface of intermediate mesoderm (IM)-derived mesonephros. Toxic environmental factors and mutations in various genes are known to disturb normal gonadal development, but because of a lack of suitable in vitro models, detailed studies characterizing the molecular basis of the observed defects have not been performed. Objective: To establish an in vitro method for studying differentiation of bipotential gonadal progenitors by using human embryonic stem cells (hESCs) and to investigate the role of bone morphogenetic protein (BMP) in gonadal differentiation...
November 1, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28862252/genome-wide-identification-of-histone-h2a-and-histone-variant-h2a-z-interacting-proteins-by-bppi-seq
#13
Yi Zhang, Wai Lim Ku, Shuai Liu, Kairong Cui, Wenfei Jin, Qingsong Tang, William Lu, Bing Ni, Keji Zhao
H2A is a nucleosome core subunit involved in organizing DNA into a chromatin structure that is often inaccessible to regulatory enzymes. Replacement of H2A by its variant H2A.Z renders chromatin accessible at enhancers and promoters. However, it remains unclear how H2A.Z functions so differently from canonical H2A. Here we report the genome-wide identification of proteins that directly interact with H2A and H2A.Z in vivo using a novel strategy, bPPI-seq. We show that bPPI-seq is a sensitive and robust technique to identify protein-protein interactions in vivo...
October 2017: Cell Research
https://www.readbyqxmd.com/read/28852936/down-regulation-of-pax2-promotes-in-vitro-differentiation-of-podocytes-from-human-cd34-cells
#14
Manne Mudhu Sunitha, Lokanathan Srikanth, Pasupuleti Santhosh Kumar, Chodimella Chandrasekhar, Potukuchi Venkata Gurunadha Krishna Sarma
Podocytes are major kidney cells that help in glomerular filtration and any damage or loss is a major event in the progression of kidney diseases. Understanding podocytes development will help in designing therapeutic strategies against these renal diseases. Therefore, in vitro generation of podocytes from adult hematopoietic CD34+ stem cells is explored in the present study. Apheretically, isolated human HSCs from peripheral blood showed the presence of CD34 surface glycoprotein through immunocytochemistry (ICC) and flowcytometry...
December 2017: Cell and Tissue Research
https://www.readbyqxmd.com/read/28743496/wnk4-is-indispensable-for-the-pathogenesis-of-pseudohypoaldosteronism-type-ii-caused-by-mutant-klhl3
#15
Koichiro Susa, Eisei Sohara, Daiei Takahashi, Tomokazu Okado, Tatemitsu Rai, Shinichi Uchida
WNK-OSR1/SPAK-NCC signaling cascade is important for regulating salt balance and blood pressure. Activation of WNK-OSR1/SPAK-NaCl cotransporter (NCC) cascade increases sodium reabsorption in the kidney, leading to pseudohypoaldosteronism type II (PHA II) characterized by salt-sensitive hypertension and hyperkalemia. It has been previously demonstrated that the amount of phosphorylated and total NCC markedly decreased in WNK4-/- mice, indicating that WNK4 plays a major role for activation of OSR1/SPAK-NCC signaling...
September 23, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28724605/heterozygous-loss-of-function-mutation-in-odd-skipped-related-1-osr1-is-associated-with-vesicoureteric-reflux-duplex-systems-and-hydronephrosis
#16
Marie-Lyne Fillion, Jasmine El Andalousi, Fatima Tokhmafshan, Vasikar Murugapoopathy, Christine L Watt, Inga J Murawski, John-Paul Capolicchio, Mohamed El-Sherbiny, Roman Jednak, Indra R Gupta
Odd-skipped related 1 (Osr1) is a transcriptional repressor that plays critical roles in maintaining the mesenchymal stem cell population within the developing kidney. Here, we report that newborn pups with a heterozygous null mutation in Osr1 exhibit a 21% incidence of vesicoureteric reflux and have hydronephrosis and urinary tract duplications. Newborn pups have a short intravesical ureter, resulting in a less competent ureterovesical junction which arises from a delay in urinary tract development. We describe a new domain of Osr1 expression in the ureteral mesenchyme and within the developing bladder in the mouse...
November 1, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28688764/relt-family-members-activate-p38-and-induce-apoptosis-by-a-mechanism-distinct-from-tnfr1
#17
Pachai Moua, Mathew Checketts, Liang-Guo Xu, Hong-Bing Shu, Mary E Reyland, John K Cusick
Receptor Expressed in Lymphoid Tissues (RELT) is a human Tumor Necrosis Factor Receptor (TNFR) family member that has two identified homologous binding partners, RELL1 and RELL2. This study sought to further understand the pattern of RELT expression, the functional role of RELT family members, and the mechanism of RELT-induced apoptosis. RELT protein expression was detected in the spleen, lymph node, brain, breast and peripheral blood leukocytes (PBLs). A smaller than expected size of RELT was observed in PBLs, suggesting a proteolytically cleaved form of RELT...
September 9, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28566208/development-of-wnk-signaling-inhibitors-as-a-new-class-of-antihypertensive-drugs
#18
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/28501478/osr1-functions-downstream-of-hedgehog-pathway-to-regulate-foregut-development
#19
Lu Han, Jingyue Xu, Emily Grigg, Megan Slack, Praneet Chaturvedi, Rulang Jiang, Aaron M Zorn
During early fetal development, paracrine Hedgehog (HH) ligands secreted from the foregut epithelium activate Gli transcription factors in the surrounding mesenchyme to coordinate formation of the respiratory system, digestive track and the cardiovascular network. Although disruptions to this process can lead to devastating congenital defects, the underlying mechanisms and downstream targets, are poorly understood. We show that the zinc finger transcription factor Osr1 is a novel HH target as Osr1 expression in the foregut mesenchyme depends on HH signaling and the effector of HH pathway Gli3 binds to a conserved genomic loci near Osr1 promoter region...
July 1, 2017: Developmental Biology
https://www.readbyqxmd.com/read/28414128/impaired-degradation-of-medullary-wnk4-in-the-kidneys-of-klhl2-knockout-mice
#20
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
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