scholarly journals Endothelin signaling via guanine exchange factor C3G in renal glomerular mesangial cellsThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research.

2010 ◽  
Vol 88 (8) ◽  
pp. 808-816 ◽  
Author(s):  
Victoriya A. Rufanova ◽  
Anna Alexanian ◽  
Tammo Ostendorf ◽  
Dirk Bokemeyer ◽  
Simon Prosser ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Kidney Development ◽  
Mesangial Cells ◽  
Biological Significance ◽  
Fiber Formation ◽  
Actin Dynamics ◽  
Glomerular Mesangial Cells ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Mesangioproliferative Glomerulonephritis

The guanine nucleotide exchange factor C3G is one of the mediators of endothelin-1 (ET-1) intracellular signaling cascades and is vital for kidney development and homeostasis. The aim of the current study was to analyze the specificity of ET-1-induced signaling via C3G in rat glomerular mesangial cells (GMC) and to investigate the biological significance of C3G during mesangioproliferative glomerulonephritis. In GMC, C3G expression was increased (1) in vivo after induction of the anti-Thy1 model of glomerulonephritis and (2) in cell culture experiments after fetal bovine serum incubation. To examine the consequences of C3G up-regulation, adenovirus-mediated gene transfer of C3G into cultured glomerular cells was done, and the GTP loading of the small G proteins Rap1 and R-Ras was analyzed. Overexpression of C3G in mesangial cells resulted in enhanced activation of Rap1, but failed to affect the GTP-bound status of R-Ras in ET-1-stimulated cells. C3G overexpression led to significant changes in GMC spreading and migration patterns in response to ET-1 stimulation and increased stress fiber formation, which was mimicked by Rap1A overexpression. Together, these findings suggest (1) the existence of regulatory mechanisms resulting in disease-related up-regulation of C3G in GMC and (2) that an increase in the C3G protein level may contribute to the resolution stage of mesangioproliferative glomerulonephritis by reducing GMC sensitivity to ET-1, modulating cellular motility, and actin dynamics.

Stimulation of pro-α1(I) collagen by TGF-β1 in mesangial cells: role of the p38 MAPK pathway

2001 ◽  
Vol 280 (3) ◽  
pp. F495-F504 ◽  
Author(s):  
Beek Yoke Chin ◽  
Amir Mohsenin ◽  
Su Xia Li ◽  
Augustine M. K. Choi ◽  
Mary E. Choi
Keyword(s):  
P38 Mapk ◽  
Intracellular Signaling ◽  
Mesangial Cells ◽  
Mapk Pathway ◽  
Dominant Negative ◽  
Glomerular Mesangial Cells ◽  
Mapk Activation ◽  
Mapk Phosphorylation ◽  
Collagen Mrna

Transforming growth factor-β1(TGF-β1) is a potent inducer of extracellular matrix protein synthesis and a key mediator of renal fibrosis. However, the intracellular signaling mechanisms by which TGF-β1stimulates this process remain incompletely understood. In this report, we examined the role of a major stress-activated intracellular signaling cascade, belonging to the mitogen-activated protein kinase (MAPK) superfamily, in mediating TGF-β1 responses in rat glomerular mesangial cells, using dominant-negative inhibition of TGF-β1 signaling receptors. We first stably transfected rat glomerular mesangial cells with a kinase-deleted mutant TGF-β type II receptor (TβR-IIM) designed to inhibit TGF-β1 signaling in a dominant-negative fashion. Next, expression of TβR-IIM mRNA was confirmed by Northern analysis. Cell surface expression and ligand binding of TβR-IIM protein were demonstrated by affinity cross-linking with 125I-labeled-TGF-β1. TGF-β1 rapidly induced p38 MAPK phosphorylation in wild-type and empty vector (pcDNA3)-transfected control mesangial cells. Interestingly, transfection with dominant-negative TβR-IIM failed to block TGF-β1-induced p38 MAPK phosphorylation. Moreover, dominant-negative TβR-IIMfailed to block TGF-β1-stimulated pro-α1(I) collagen mRNA expression and cellular protein synthesis, whereas TGF-β1-induced extracellular signal-regulated kinase (ERK) 1/ERK2 activation and antiproliferative responses were blocked by TβR-IIM. In the presence of a specific inhibitor of p38 MAPK, SB-203580, TGF-β1 was unable to stimulate pro-α1(I) collagen mRNA expression in the control and TβR-IIM-transfected mesangial cells. Finally, we confirmed that both p38 MAPK activation and pro-α1(I) collagen stimulation were TGF-β1 effects that were abrogated by dominant-negative inhibition of TGF-β type I receptor. Thus we show first demonstration of p38 MAPK activation by TGF-β1 in mesangial cells, and, given the rapid kinetics, this TGF-β1 effect is likely a direct one. Furthermore, our findings suggest that the p38 MAPK pathway functions as a component in the signaling of pro-α1(I) collagen induction by TGF-β1 in mesangial cells.

Human p63RhoGEF, a novel RhoA-specific guanine nucleotide exchange factor, is localized in cardiac sarcomere

2002 ◽  
Vol 115 (3) ◽  
pp. 629-640 ◽  
Author(s):  
Michel Souchet ◽  
Elodie Portales-Casamar ◽  
David Mazurais ◽  
Susanne Schmidt ◽  
Isabelle Léger ◽  
...  
Keyword(s):  
Guanine Nucleotide Exchange Factor ◽  
Small Gtpases ◽  
Fiber Formation ◽  
Pleckstrin Homology Domain ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Intact Cells ◽  
Exchange Factor ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor

The Rho small GTPases are crucial proteins involved in regulation of signal transduction cascades from extracellular stimuli to cell nucleus and cytoskeleton. It has been reported that these GTPases are directly associated with cardiovascular disorders. In this context, we have searched for novel modulators of Rho GTPases, and here we describe p63RhoGEF a new Db1-like guanine nucleotide exchange factor (GEF). P63RhoGEF encodes a 63 kDa protein containing a Db1 homology domain in tandem with a pleckstrin homology domain and is most closely related to the second Rho GEF domain of Trio. Northern blot and in situ analysis have shown that p63RhoGEF is mainly expressed in heart and brain. In vitro guanine nucleotide exchange assays have shown that p63RhoGEF specifically acts on RhoA. Accordingly, p63RhoGEF expression induces RhoA-dependent stress fiber formation in fibroblasts and in H9C2 cardiac myoblasts. Moreover, we show that p63RhoGEF activation of RhoA in intact cells is dependent on the presence of the PH domain. Using a specific anti-p63RhoGEF antibody, we have detected the p63RhoGEF protein by immunocytochemistry in human heart and brain tissue sections. Confocal microscopy shows that p63RhoGEF is located in the sarcomeric I-band mainly constituted of cardiac sarcomeric actin. Together, these results show that p63RhoGEF is a RhoA-specific GEF that may play a key role in actin cytoskeleton reorganization in different tissues, especially in heart cellular morphology.

Role of Rho and myosin phosphorylation in actin stress fiber assembly in mesangial cells

1997 ◽  
Vol 273 (2) ◽  
pp. F283-F288 ◽  
Author(s):  
J. I. Kreisberg ◽  
N. Ghosh-Choudhury ◽  
R. A. Radnik ◽  
M. A. Schwartz
Keyword(s):  
Cell Shape ◽  
Mesangial Cells ◽  
Stress Fiber ◽  
Fiber Formation ◽  
Stress Fibers ◽  
Actin Stress Fiber ◽  
Glomerular Mesangial Cells ◽  
Fiber Assembly ◽  
Camp Elevation ◽  
Actin Stress Fibers

Treatment of renal glomerular mesangial cells with adenosine 3',5'-cyclic monophosphate (cAMP)-elevating agents induces actin stress fiber disassembly, myosin light chain (MLC) dephosphorylation, loss of adhesion to the substratum and cell shape change [J. I. Kreisberg and M. A. Venkatachalam. Am. J. Physiol. 251 (Cell Physiol. 20): C505-C511, 1986]. Thrombin and vasopressin block the effects of cAMP. Because these agents are known to promote stress fiber formation via the small GTP-binding protein Rho, we investigated the effect of an activated variant of Rho on the response to cAMP elevation. Microinjecting V14-Rho completely blocked the effect of cAMP elevation on cell shape and the actin cytoskeleton, whereas inactivating Rho with botulinum C3 exoenzyme induced stress fiber disruption and cell retraction that was indistinguishable from that caused by elevations in intracellular levels of cAMP. Disruption of actin stress fibers by cAMP has previously been ascribed to MLC dephosphorylation; however, both C3 and cytochalasin D also caused dephosphorylation of MLC, whereas blocking MLC dephosphorylation failed to block the cAMP-induced loss of actin stress fibers. We conclude that Rho can modulate the effects of cAMP elevation and suggest that MLC dephosphorylation may be a consequence of actin stress fiber disassembly.

Role of the JAK/STAT signaling pathway in diabetic nephropathy

2006 ◽  
Vol 290 (4) ◽  
pp. F762-F768 ◽  
Author(s):  
Mario B. Marrero ◽  
Amy K. Banes-Berceli ◽  
David M. Stern ◽  
Douglas C. Eaton
Keyword(s):  
Diabetic Nephropathy ◽  
High Glucose ◽  
Intracellular Signaling ◽  
Mesangial Cells ◽  
Janus Kinase ◽  
Cellular Growth ◽  
Ang Ii ◽  
Glomerular Mesangial Cells ◽  
Stat Signaling ◽  
Vasoactive Peptide

Excessive cellular growth is a major contributor to pathological changes associated with diabetic nephropathy. In particular, high glucose-induced growth of glomerular mesangial cells is a characteristic feature of diabetes-induced renal complications. Glomerular mesangial cells respond to traditional growth factors, although in diabetes this occurs in the context of an environment enriched in both circulating vasoactive mediators and high glucose. For example, the vasoactive peptide ANG II has been implicated in the pathogenesis of diabetic renal disease, and recent findings suggest that high glucose and ANG II activate intracellular signaling processes, including the polyol pathway and generation of reactive oxygen species. These pathways activate the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling cascades in glomerular mesangial cells. Activation of the JAK/STAT signaling cascade can stimulate excessive proliferation and growth of glomerular mesangial cells, contributing to diabetic nephropathy. This review focuses on some of the key elements in the diabetic microenvironment, especially high glucose and the accumulation of advanced glycoxidation end products and considers their impact on ANG II and other vasoactive peptide-mediated signaling events in vitro and in vivo.

Protein kinase Cα participates in activation of store-operated Ca2+ channels in human glomerular mesangial cells

2002 ◽  
Vol 283 (5) ◽  
pp. C1390-C1398 ◽  
Author(s):  
Rong Ma ◽  
Patrick E. Kudlacek ◽  
Steven C. Sansom
Keyword(s):  
Protein Kinase ◽  
Intracellular Signaling ◽  
Single Channel ◽  
Mesangial Cells ◽  
Glomerular Mesangial Cells ◽  
Membrane Expression ◽  
Intracellular Signaling Pathway ◽  
Single Channel Analysis ◽  
Protein Kinase Cα ◽  
Channel Analysis

Protein kinase C (PKC) plays an important role in activating store-operated Ca2+ channels (SOC) in human mesangial cells (MC). The present study was performed to determine the specific isoform(s) of conventional PKC involved in activating SOC in MC. Fura 2 fluorescence ratiometry showed that the thapsigargin-induced Ca2+ entry (equivalent to SOC) was significantly inhibited by 1 μM Gö-6976 (a specific PKCα and βI inhibitor) and PKCα antisense treatment (2.5 nM for 24–48 h). However, LY-379196 (PKCβ inhibitor) and 2,2′,3,3′,4,4′-hexahydroxy-1,1′-biphenyl-6,6′-dimethanoldimethyl ether (HBDDE; PKCα and γ inhibitor) failed to affect thapsigargin-evoked activation of SOC. Single-channel analysis in the cell-attached configuration revealed that Gö-6976 and PKCα antisense significantly depressed thapsigargin-induced activation of SOC. However, LY-379196 and HBDDE did not affect the SOC responses. In inside-out patches, application of purified PKCα or βI, but not βII or γ, significantly rescued SOC from postexcision rundown. Western blot analysis revealed that thapsigargin evoked a decrease in cytosolic expression with a corresponding increase in membrane expression of PKCα and γ. However, the translocation from cytosol to membranes was not detected for PKCβI or βII. These results suggest that PKCα participates in the intracellular signaling pathway for activating SOC upon release of intracellular stores of Ca2+.

scholarly journals Gata3Hypomorphic Mutant Mice Rescued with a Yeast Artificial Chromosome Transgene Suffer a Glomerular Mesangial Cell Defect

2016 ◽  
Vol 36 (17) ◽  
pp. 2272-2281 ◽  
Author(s):  
Takashi Moriguchi ◽  
Lei Yu ◽  
Akihito Otsuki ◽  
Keiko Ainoya ◽  
Kim-Chew Lim ◽  
...  
Keyword(s):  
Kidney Development ◽  
Yeast Artificial Chromosome ◽  
Mesangial Cells ◽  
Critical Role ◽  
Artificial Chromosome ◽  
Mutant Mice ◽  
Renal Tubules ◽  
Glomerular Mesangial Cells ◽  
Renal Hypoplasia ◽  
Transgenic Mouse Line

GATA3 is a zinc finger transcription factor that plays a crucial role in embryonic kidney development, while its precise functions in the adult kidney remain largely unexplored. Here, we demonstrate that GATA3 is specifically expressed in glomerular mesangial cells and plays a critical role in the maintenance of renal glomerular function. Newly generatedGata3hypomorphic mutant mice exhibited neonatal lethality associated with severe renal hypoplasia. Normal kidney size was restored by breeding the hypomorphic mutant with a rescuing transgenic mouse line bearing a 662-kbGata3yeast artificial chromosome (YAC), and these animals (termed G3YR mice) survived to adulthood. However, most of the G3YR mice showed degenerative changes in glomerular mesangial cells, which deteriorated progressively during postnatal development. Consequently, the G3YR adult mice suffered severe renal failure. We found that the 662-kbGata3YAC transgene recapitulatedGata3expression in the renal tubules but failed to direct sufficient GATA3 activity to mesangial cells. Renal glomeruli of the G3YR mice had significantly reduced amounts of platelet-derived growth factor receptor (PDGFR), which is known to participate in the development and maintenance of glomerular mesangial cells. These results demonstrate a critical role for GATA3 in the maintenance of mesangial cells and its absolute requirement for prevention of glomerular disease.

scholarly journals Counteractive effects of HGF on PDGF-induced mesangial cell proliferation in a rat model of glomerulonephritis

2003 ◽  
Vol 284 (6) ◽  
pp. F1171-F1180 ◽  
Author(s):  
Kazuhiko Bessho ◽  
Shinya Mizuno ◽  
Kunio Matsumoto ◽  
Toshikazu Nakamura
Keyword(s):  
Cell Proliferation ◽  
Dna Synthesis ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Suppressive Effect ◽  
Inhibitory Effect ◽  
Negative Regulator ◽  
Glomerular Mesangial Cells ◽  
Mesangial Cell Proliferation ◽  
Mesangioproliferative Glomerulonephritis

Activation and proliferation of glomerular mesangial cells play an important role in the development of mesangioproliferative glomerulonephritis. We investigated the role of hepatocyte growth factor (HGF) in regulating activated mesangial cell proliferation. In glomeruli of normal rats, mesangial cells barely expressed the c-Met/HGF receptor. However, when mesangioproliferative glomerulonephritis was induced in rats by the administration of an anti-Thy 1.1 antibody, glomerular HGF expression transiently decreased along with mesangiolysis, and activation of mesangial cells was associated with upregulation of the c-Met receptor. Activated mesangial cells in culture also expressed the c-Met/HGF receptor. Although addition of HGF to cultured mesangial cells did not increase DNA synthesis, HGF did diminish PDGF-induced DNA synthesis. PDGF induced activation of ERK, which continued for at least 48 h. When PDGF and HGF were simultaneously added, HGF inhibited the prolonged activation of ERK, which suggests that early inactivation of PDGF-induced ERK may be involved in the inhibitory effect of HGF on mesangial cell proliferation. Furthermore, administration of HGF to rats with anti-Thy 1.1 nephritis resulted in a selective suppression of activated mesangial cell proliferation, and this suppressive effect was associated with attenuation of phosphorylated glomerular ERK. These results indicate that HGF counteracts PDGF-induced mesangial cell proliferation and functions as a negative regulator of activated mesangial cell proliferation.

scholarly journals TIAM-1/GEF can shape somatosensory dendrites independently of its GEF activity by regulating F-actin localization

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Leo TH Tang ◽  
Carlos A Diaz-Balzac ◽  
Maisha Rahman ◽  
Nelson J Ramirez-Suarez ◽  
Yehuda Salzberg ◽  
...  
Keyword(s):  
Guanine Nucleotide Exchange Factor ◽  
Actin Dynamics ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Dendritic Arbors ◽  
Actin Localization ◽  
Redundant Pathway

Dendritic arbors are crucial for nervous system assembly, but the intracellular mechanisms that govern their assembly remain incompletely understood. Here, we show that the dendrites of PVD neurons in Caenorhabditis elegans are patterned by distinct pathways downstream of the DMA-1 leucine-rich transmembrane (LRR-TM) receptor. DMA-1/LRR-TM interacts through a PDZ ligand motif with the guanine nucleotide exchange factor TIAM-1/GEF in a complex with act-4/Actin to pattern higher order 4° dendrite branches by localizing F-actin to the distal ends of developing dendrites. Surprisingly, TIAM-1/GEF appears to function independently of Rac1 guanine nucleotide exchange factor activity. A partially redundant pathway, dependent on HPO-30/Claudin, regulates formation of 2° and 3° branches, possibly by regulating membrane localization and trafficking of DMA-1/LRR-TM. Collectively, our experiments suggest that HPO-30/Claudin localizes the DMA-1/LRR-TM receptor on PVD dendrites, which in turn can control dendrite patterning by directly modulating F-actin dynamics through TIAM-1/GEF.

scholarly journals The Rho-guanine nucleotide exchange factor PDZ-RhoGEF governs susceptibility to diet-induced obesity and type 2 diabetes

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Ying-Ju Chang ◽  
Scott Pownall ◽  
Thomas E Jensen ◽  
Samar Mouaaz ◽  
Warren Foltz ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Guanine Nucleotide Exchange Factor ◽  
Fiber Formation ◽  
Proliferative Potential ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Guanine Nucleotide Exchange ◽  
Diet Induced Obesity ◽  
Nucleotide Exchange Factor

Adipose tissue is crucial for the maintenance of energy and metabolic homeostasis and its deregulation can lead to obesity and type II diabetes (T2D). Using gene disruption in the mouse, we discovered a function for a RhoA-specific guanine nucleotide exchange factor PDZ-RhoGEF (Arhgef11) in white adipose tissue biology. While PDZ-RhoGEF was dispensable for a number of RhoA signaling-mediated processes in mouse embryonic fibroblasts, including stress fiber formation and cell migration, it's deletion led to a reduction in their proliferative potential. On a whole organism level, PDZ-RhoGEF deletion resulted in an acute increase in energy expenditure, selectively impaired early adipose tissue development and decreased adiposity in adults. PDZ-RhoGEF-deficient mice were protected from diet-induced obesity and T2D. Mechanistically, PDZ-RhoGEF enhanced insulin/IGF-1 signaling in adipose tissue by controlling ROCK-dependent phosphorylation of the insulin receptor substrate-1 (IRS-1). Our results demonstrate that PDZ-RhoGEF acts as a key determinant of mammalian metabolism and obesity-associated pathologies.

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