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Nedd4-2

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https://www.readbyqxmd.com/read/29108451/nedd4-2-dependent-control-of-na-homeostasis-and-renal-disease
#1
Jantina A Manning, Tanya L Henshall, Sharad Kumar
No abstract text is available yet for this article.
November 6, 2017: Cell Cycle
https://www.readbyqxmd.com/read/29039560/20-hydroxyeicosatetraenoic-acid-regulates-the-expression-of-nedd4%C3%A2-2-in-kidney-and-liver-through-a-neddylation-modification-pathway
#2
Jianzhu Zhao, Bijun Zhang, Guangrui Lai, Runhong Xu, Guoming Chu, Yanyan Zhao
The present study aimed to test whether 20-hydroxyeicosatetraenoic acid (20‑HETE) affected neddylation modification of E3‑ligase Nedd4‑2 (neural precursor cell expressed, developmentally down‑regulated 4‑like, E3 ubiquitin protein ligase). A cytochrome P450 family 4 subfamily F member 2 (CYP4F2) transgenic mouse model that overproduces 20‑HETE in the kidney and the liver was used in the present study. Transgenic mice with high salt intake exhibited increased activation of Nedd4‑2‑mediated ubiquitin‑proteasome pathway...
December 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28972136/the-mechanism-of-neural-precursor-cell-expressed-developmentally-down-regulated-4-2-nedd4-2-nedd4l-catalyzed-polyubiquitin-chain-assembly
#3
Dustin R Todaro, Allison C Augustus-Wallace, Jennifer M Klein, Arthur L Haas
The mechanism of Nedd4-2 has been quantitatively explored for the first time using biochemically-defined kinetic assays examining rates of (125)I-polyubiquitin chain assembly as a functional readout. We demonstrate that Nedd4-2 exhibits broad specificity for E2 paralogs of the Ubc4/5 clade to assemble Lys(63)-linked polyubiquitin chains. Full length Nedd4-2 catalyzes free (125)I-polyubiquitin chain assembly by hyperbolic Michaelis-Menten kinetics with respect to Ubc5B∼ubiquitin thioester concentration (KM = 44 ± 6 nM; kcat = 0...
September 28, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28862701/deletion-of-nedd4-2-results-in-progressive-kidney-disease-in-mice
#4
Tanya L Henshall, Jantina A Manning, Omri S Alfassy, Pranay Goel, Natasha A Boase, Hiroshi Kawabe, Sharad Kumar
NEDD4-2 (NEDD4L), a ubiquitin protein ligase of the Nedd4 family, is a key regulator of cell surface expression and activity of the amiloride-sensitive epithelial Na(+) channel (ENaC). While hypomorphic alleles of Nedd4-2 in mice show salt-sensitive hypertension, complete knockout results in pulmonary distress and perinatal lethality due to increased cell surface levels of ENaC. We now show that Nedd4-2 deficiency in mice also results in an unexpected progressive kidney injury phenotype associated with elevated ENaC and Na(+)Cl(-) cotransporter expression, increased Na(+) reabsorption, hypertension and markedly reduced levels of aldosterone...
September 1, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28613240/an-isoform-of-nedd4-2-plays-a-pivotal-role-in-electrophysiological-cardiac-abnormalities
#5
Shintaro Minegishi, Tomoaki Ishigami, Hisho Kawamura, Tabito Kino, Lin Chen, Rie Nakashima-Sasaki, Hiroshi Doi, Kengo Azushima, Hiromichi Wakui, Yumi Chiba, Kouichi Tamura
We have previously shown that neural precursor cell-expressed developmentally downregulated gene 4-2 (Nedd4-2) isoforms with a C2 domain are closely related to ubiquitination of epithelial sodium channel (ENaC), resulting in salt-sensitive hypertension by Nedd4-2 C2 targeting in mice. The sodium voltage-gated channel alpha subunit 5 (SCN5A) gene encodes the α subunit of the human cardiac voltage-gated sodium channel (I Na), and the potassium voltage-gated channel subfamily H member 2 (KCNH2) gene encodes rapidly activating delayed rectifier K channels (I Kr)...
June 14, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28608480/sgk1-nedd4-2-signaling-pathway-regulates-the-activity-of-human-organic-anion-transporters-3
#6
Haoxun Wang, Guofeng You
Human organic anion transporter 3 (hOAT3) is localized at the basolateral membrane of renal proximal tubule cells and facilitates the renal secretion of numerous clinical drugs, including anti-HIV therapeutics, anti-tumor drugs, antibiotics, antihypertension drugs and anti-inflammatories. The present study explored the role of serum and glucocorticoid-inducible kinase 1 (sgk1) in the regulation of hOAT3. It was shown that over-expression of sgk1 in hOAT3-expressing cells stimulated hOAT3 transport activity by enhancing the transporter expression at the plasma membrane, kinetically reflected as an increased maximal transport velocity Vmax without substantial change in the substrate-binding affinity Km ...
November 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28604611/eplerenone-resistant-salt-sensitive-hypertension-in-nedd4-2-c2-ko-mice
#7
Tabito Kino, Tomoaki Ishigami, Tsumugi Murata, Hiroshi Doi, Rie Nakashima-Sasaki, Lin Chen, Michiko Sugiyama, Kengo Azushima, Hiromichi Wakui, Shintaro Minegishi, Kouichi Tamura
The epithelial sodium channel (ENaC) plays critical roles in maintaining fluid and electrolyte homeostasis and is located in the aldosterone-sensitive distal nephron (ASDN). We previously found that Nedd4-2 C2 knockout (KO) mice showed salt-sensitive hypertension with paradoxically enhanced ENaC gene expression in ASDN under high oral salt intake. Eplerenone (EPL), a selective aldosterone blocker, is a promising therapeutic option for resistant or/and salt-sensitive hypertension. We examined the effect of EPL on Nedd4-2 C2 KO mice with respect to blood pressure, metabolic parameters, and molecular level changes in ASDN under high oral salt intake...
June 11, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28588583/hypercapnia-impairs-enac-cell-surface-stability-by-promoting-phosphorylation-polyubiquitination-and-endocytosis-of-%C3%AE-enac-in-a-human-alveolar-epithelial-cell-line
#8
Paulina Gwoździńska, Benno A Buchbinder, Konstantin Mayer, Susanne Herold, Rory E Morty, Werner Seeger, István Vadász
Acute lung injury is associated with formation of pulmonary edema leading to impaired gas exchange. Patients with acute respiratory distress syndrome (ARDS) require mechanical ventilation to improve oxygenation; however, the use of relatively low tidal volumes (to minimize further injury of the lung) often leads to further accumulation of carbon dioxide (hypercapnia). Hypercapnia has been shown to impair alveolar fluid clearance (AFC), thereby causing retention of pulmonary edema, and may lead to worse outcomes; however, the underlying molecular mechanisms remain incompletely understood...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28572241/pkc-nedd4-2-signaling-pathway-regulates-the-cell-surface-expression-of-drug-transporter-hoat1
#9
Da Xu, Jinghui Zhang, Qiang Zhang, Yunzhou Fan, Chenchang Liu, Guofeng You
Human organic anion transporter-1 (hOAT1) regulates the absorption, distribution, and excretion of a wide range of clinically important drugs. Our previous work demonstrated that hOAT1 is a dynamic membrane transporter, constitutively internalizing from and recycling back to the cell plasma membrane. Short-term activation (<30 minutes) of protein kinase C (PKC) promotes the attachment of a lysine 48-linked polyubiquitin chain to hOAT1, a process catalyzed by ubiquitin ligase neural precursor cell expressed developmentally down-regulated 4-2 (Nedd4-2)...
August 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28539383/glomerulosclerosis-induced-by-deficiency-of-membrane-associated-guanylate-kinase-inverted-2-in-kidney-podocytes
#10
Naritoshi Shirata, Kan-Ichiro Ihara, Kanae Yamamoto-Nonaka, Takuto Seki, Shin-Ichi Makino, Juan Alejandro Oliva Trejo, Takafumi Miyake, Hiroyuki Yamada, Kirk Nicholas Campbell, Takahiko Nakagawa, Kiyoshi Mori, Motoko Yanagita, Peter Mundel, Katsuhiko Nishimori, Katsuhiko Asanuma
Membrane-associated guanylate kinase inverted 2 (MAGI-2) is a component of the slit diaphragm (SD) of glomerular podocytes. Here, we investigated the podocyte-specific function of MAGI-2 using newly generated podocyte-specific MAGI-2-knockout (MAGI-2-KO) mice. Compared with podocytes from wild-type mice, podocytes from MAGI-2-KO mice exhibited SD disruption, morphologic abnormalities of foot processes, and podocyte apoptosis leading to podocyte loss. These pathologic changes manifested as massive albuminuria by 8 weeks of age and glomerulosclerosis and significantly higher plasma creatinine levels at 12 weeks of age; all MAGI-2-KO mice died by 20 weeks of age...
September 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28383056/involvement-of-epithelial-na-channel-in-the-elevated-myogenic-response-in-posterior-cerebral-arteries-from-spontaneously-hypertensive-rats
#11
Soo-Kyoung Choi, Soo-In Yeon, Youngin Kwon, Seonhee Byeon, Young-Ho Lee
Hypertension is characterized by increased peripheral vascular resistance which is related with elevated myogenic response. Recent findings have indicated that epithelial sodium channel (ENaC) is involved in mechanotransduction of the myogenic response. The purpose of this study was to investigate the involvement of ENaC in the elevated myogenic response of posterior cerebral arteries (PCAs) from spontaneously hypertensive rats (SHRs). Sixteen to eighteen weeks old male wistar kyoto rats (WKYs) and SHRs were used in this study...
April 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28296171/calcium-dependent-nedd4-2-upregulation-mediates-degradation-of-the-cardiac-sodium-channel-nav1-5-implications-for-heart-failure
#12
L Luo, F Ning, Y Du, B Song, D Yang, S C Salvage, Y Wang, J A Fraser, S Zhang, A Ma, T Wang
AIM: Reductions in voltage-gated sodium channel (Nav1.5) function/expression provide a slowed-conduction substrate for cardiac arrhythmias. Nedd4-2, which is activated by calcium, post-translationally modulates Nav1.5. We aim to investigate whether elevated intracellular calcium ([Ca(2+) ]i ) reduces Nav1.5 through Nedd4-2 and its role in heart failure (HF). METHODS: Using a combination of biochemical, electrophysiological, cellular and in vivo methods, we tested the effect and mechanism of calcium on Nedd4-2 and in turn Nav1...
September 2017: Acta Physiologica
https://www.readbyqxmd.com/read/28289184/renal-tubular-ubiquitin-protein-ligase-nedd4-2-is-required-for-renal-adaptation-during-long-term-potassium-depletion
#13
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...
August 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28218740/maresin1-stimulates-alveolar-fluid-clearance-through-the-alveolar-epithelial-sodium-channel-na-k-atpase-via-the-alx-pi3k-nedd4-2-pathway
#14
Jun-Li Zhang, Xiao-Jun Zhuo, Jing Lin, Ling-Chun Luo, Wei-Yang Ying, Xiang Xie, Hua-Wei Zhang, Jing-Xiang Yang, Dan Li, Fang Gao Smith, Sheng-Wei Jin
Maresin1 (MaR1) is a new docosahexaenoic acid-derived pro-resolving agent that promotes the resolution of inflammation. In this study, we sought to investigate the effect and underlining mechanisms of MaR1 in modulating alveolar fluid clearance (AFC) on LPS-induced acute lung injury. MaR1 was injected intravenously or administered by instillation (200 ng/kg) 8 h after LPS (14 mg/kg) administration and AFC was measured in live rats. In primary rat alveolar type II epithelial cells, MaR1 (100 nM) was added to the culture medium with lipopolysaccharide for 6 h...
May 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/28212375/epilepsy-associated-gene-nedd4-2-mediates-neuronal-activity-and-seizure-susceptibility-through-ampa-receptors
#15
Jiuhe Zhu, Kwan Young Lee, Kathryn A Jewett, Heng-Ye Man, Hee Jung Chung, Nien-Pei Tsai
The neural precursor cell expressed developmentally down-regulated gene 4-2, Nedd4-2, is an epilepsy-associated gene with at least three missense mutations identified in epileptic patients. Nedd4-2 encodes a ubiquitin E3 ligase that has high affinity toward binding and ubiquitinating membrane proteins. It is currently unknown how Nedd4-2 mediates neuronal circuit activity and how its dysfunction leads to seizures or epilepsies. In this study, we provide evidence to show that Nedd4-2 mediates neuronal activity and seizure susceptibility through ubiquitination of GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, (AMPAR)...
February 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28192531/multi-layered-control-of-galectin-8-mediated-autophagy-during-adenovirus-cell-entry-through-a-conserved-ppxy-motif-in-the-viral-capsid
#16
Charlotte Montespan, Shauna A Marvin, Sisley Austin, Andrew M Burrage, Benoit Roger, Fabienne Rayne, Muriel Faure, Edward M Campell, Carola Schneider, Rudolph Reimer, Kay Grünewald, Christopher M Wiethoff, Harald Wodrich
Cells employ active measures to restrict infection by pathogens, even prior to responses from the innate and humoral immune defenses. In this context selective autophagy is activated upon pathogen induced membrane rupture to sequester and deliver membrane fragments and their pathogen contents for lysosomal degradation. Adenoviruses, which breach the endosome upon entry, escape this fate by penetrating into the cytosol prior to autophagosome sequestration of the ruptured endosome. We show that virus induced membrane damage is recognized through Galectin-8 and sequesters the autophagy receptors NDP52 and p62...
February 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28186199/ubiquitination-mediates-kv1-3-endocytosis-as-a-mechanism-for-protein-kinase-c-dependent-modulation
#17
Ramón Martínez-Mármol, Katarzyna Styrczewska, Mireia Pérez-Verdaguer, Albert Vallejo-Gracia, Núria Comes, Alexander Sorkin, Antonio Felipe
The voltage-dependent potassium channel Kv1.3 plays essential physiological functions in the immune system. Kv1.3, regulating the membrane potential, facilitates downstream Ca(2+) -dependent pathways and becomes concentrated in specific membrane microdomains that serve as signaling platforms. Increased and/or delocalized expression of the channel is observed at the onset of several autoimmune diseases. In this work, we show that adenosine (ADO), which is a potent endogenous modulator, stimulates PKC, thereby causing immunosuppression...
February 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28182002/rapamycin-upregulates-glutamate-transporter-and-il-6-expression-in-astrocytes-in-a-mouse-model-of-parkinson-s-disease
#18
Yunlong Zhang, Xiaoliang He, Xiaojuan Wu, Ming Lei, Zhiyun Wei, Xiuping Zhang, Lei Wen, Pingyi Xu, Shaomin Li, Shaogang Qu
Rapamycin protects mice against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced loss of dopaminergic neurons, which is an established model for Parkinson's disease. We demonstrated that rapamycin preserves astrocytic expression of glutamate transporters and glutamate reuptake. The protective effect was also observed in astrocyte cultures, indicating that rapamycin acts directly on astrocytes. In the MPTP model, rapamycin caused reduced expression of the E3 ubiquitin ligase Nedd4-2 (neuronal precursor cell expressed developmentally downregulated 4-2) and reduced colocalization of glutamate transporters with ubiquitin...
February 9, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28151476/regulation-of-glutamate-transporter-trafficking-by-nedd4-2-in-a-parkinson-s-disease-model
#19
Yunlong Zhang, Xiaoliang He, Xingjun Meng, Xiaojuan Wu, Huichun Tong, Xiuping Zhang, Shaogang Qu
Glutamate transporters play a key role in glutamate clearance and protect the central nervous system from glutamate excitotoxicity. Dysfunctional glutamate transporters contribute to the pathogenesis of Parkinson's disease (PD); however, the mechanisms that underlie the regulation of glutamate transporters in PD are still not well characterized. Here we report that Nedd4-2 mediates the ubiquitination of glutamate transporters in 1-methyl-4- phenylpyridinium (MPP(+))-treated astrocytes and in the midbrain of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-constructed PD model mice...
February 2, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28087701/the-ubiquitin-ligase-nedd4l-regulates-the-na-k-2cl-co-transporter-nkcc1-slc12a2-in-the-colon
#20
Chong Jiang, Hiroshi Kawabe, Daniela Rotin
The ubiquitin ligase Nedd4-like (Nedd4L, or Nedd4-2) binds to and regulates stability of the epithelial Na(+) channel (ENaC) in salt-absorbing epithelia in the kidney, lung, and other tissues. Its role in the distal colon, which also absorbs salt and fluid and expresses ENaC, is unknown. Using a conditional knock-out approach to knock out Nedd4L in mice intestinal epithelium (Nedd4L(f/f) ;Vil-Cre(ERT2) ) we show here that Nedd4L depletion leads to a higher steady-state short circuit current (Isc) in mouse distal colon tissue relative to controls...
February 24, 2017: Journal of Biological Chemistry
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