The small GTPase Rac-1 is a regulator of mesangial cell morphology and thrombospondin-1 expression

Giehl, Klaudia; Graneß, Angela; Goppelt‐Struebe, Margarete

doi:10.1152/ajprenal.00093.2007

Cited by 15 publications

(12 citation statements)

References 54 publications

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“…Hence Rac1, rather than RhoA, is the primary mediator of cAMP-dependent inhibition of Egr1 expression in VSMC. This is consistent with previous work demonstrating distinct functional roles of these GTPases on gene expression [33] and an essential role for Rac1 for VSMC proliferation and intima formation in vivo [14]. We demonstrate that expression of constitutively-active Rac1 rescues SRE-activity and Egr1 expression after cAMP-stimulation, consistent with previous work linking Rac1 activity to SRF-dependent gene expression in fibroblasts [34].…”

Section: Discussionsupporting

confidence: 92%

Inhibition of Egr1 expression underlies the anti-mitogenic effects of cAMP in vascular smooth muscle cells

Kimura

Duggirala

Hindmarch

et al. 2014

Journal of Molecular and Cellular Cardiology

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AimsCyclic AMP inhibits vascular smooth muscle cell (VSMC) proliferation which is important in the aetiology of numerous vascular diseases. The anti-mitogenic properties of cAMP in VSMC are dependent on activation of protein kinase A (PKA) and exchange protein activated by cAMP (EPAC), but the mechanisms are unclear.Methods and resultsSelective agonists of PKA and EPAC synergistically inhibited Egr1 expression, which was essential for VSMC proliferation. Forskolin, adenosine, A2B receptor agonist BAY60-6583 and Cicaprost also inhibited Egr1 expression in VSMC but not in endothelial cells. Inhibition of Egr1 by cAMP was independent of cAMP response element binding protein (CREB) activity but dependent on inhibition of serum response element (SRE) activity. SRF binding to the Egr1 promoter was not modulated by cAMP stimulation. However, Egr1 expression was dependent on the SRF co-factors Elk1 and 4 but independent of MAL. Inhibition of SRE-dependent Egr1 expression was due to synergistic inhibition of Rac1 activity by PKA and EPAC, resulting in rapid cytoskeleton remodelling and nuclear export of ERK1/2. This was associated with de-phosphorylation of the SRF co-factor Elk1.ConclusioncAMP inhibits VSMC proliferation by rapidly inhibiting Egr1 expression. This occurs, at least in part, via inhibition of Rac1 activity leading to rapid actin-cytoskeleton remodelling, nuclear export of ERK1/2, impaired Elk1-phosphorylation and inhibition of SRE activity. This identifies one of the earliest mechanisms underlying the anti-mitogenic effects of cAMP in VSMC but not in endothelial cells, making it an attractive target for selective inhibition of VSMC proliferation.

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Section: Discussionsupporting

confidence: 92%

Inhibition of Egr1 expression underlies the anti-mitogenic effects of cAMP in vascular smooth muscle cells

Kimura

Duggirala

Hindmarch

et al. 2014

Journal of Molecular and Cellular Cardiology

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“…CTGF is an important mediator of TGF-β signaling in the heart and abnormal expression of this gene has been used as a diagnostic marker for cardiac fibrosis [47]. TSP1 can activate latent TGF-β by stimulation of growth factors such as Ang II and endothelin-1 (ET-1) [48,49]. Both CTGF and TSP1 are up regulated by TGF-β [50].…”

Section: Discussionmentioning

confidence: 99%

Pathophysiological Defects and Transcriptional Profiling in the RBM20-/- Rat Model

et al. 2013

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Our recent study indicated that RNA binding motif 20 (Rbm20) alters splicing of titin and other genes. The current goals were to understand how the Rbm20-/- rat is related to physiological, structural, and molecular changes leading to heart failure. We quantitatively and qualitatively compared the expression of titin isoforms between Rbm20-/- and wild type rats by real time RT-PCR and SDS agarose electrophoresis. Isoform changes were linked to alterations in transcription as opposed to translation of titin messages. Reduced time to exhaustion with running in knockout rats also suggested a lower maximal cardiac output or decreased skeletal muscle performance. Electron microscopic observations of the left ventricle from knockout animals showed abnormal myofibril arrangement, Z line streaming, and lipofuscin deposits. Mutant skeletal muscle ultrastructure appeared normal. The results suggest that splicing alterations in Rbm20-/- rats resulted in pathogenic changes in physiology and cardiac ultrastructure. Secondary changes were observed in message levels for many genes whose splicing was not directly affected. Gene and protein expression data indicated the activation of pathophysiological and muscle stress-activated pathways. These data provide new insights on Rbm20 function and how its malfunction leads to cardiomyopathy.

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“…TSP-1 can bind and activate integrin receptors to mediate neurite outgrowth [28], and some studies suggest that TSP-1 can reorganize the actin cytoskeleton through stimulation of phosphoinositide 3-kinase (PI3-K) [87]. TSP-1 can also induce changes in cell morphology through activation of the Src family of kinases, ERK 1/2 or Rac-1 [88]. In addition, many effects of TSP-1 as inhibitor of angiogenesis and tumor growth are mediated by nitric oxide [89], p38 MAPK [90], PI3-K, FAK [91] and the CD36 receptor [92].…”

Section: Discussionmentioning

confidence: 99%

A Role for Thrombospondin-1 Deficits in Astrocyte-Mediated Spine and Synaptic Pathology in Down's Syndrome

et al. 2010

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BackgroundDown's syndrome (DS) is the most common genetic cause of mental retardation. Reduced number and aberrant architecture of dendritic spines are common features of DS neuropathology. However, the mechanisms involved in DS spine alterations are not known. In addition to a relevant role in synapse formation and maintenance, astrocytes can regulate spine dynamics by releasing soluble factors or by physical contact with neurons. We have previously shown impaired mitochondrial function in DS astrocytes leading to metabolic alterations in protein processing and secretion. In this study, we investigated whether deficits in astrocyte function contribute to DS spine pathology.Methodology/Principal FindingsUsing a human astrocyte/rat hippocampal neuron coculture, we found that DS astrocytes are directly involved in the development of spine malformations and reduced synaptic density. We also show that thrombospondin 1 (TSP-1), an astrocyte-secreted protein, possesses a potent modulatory effect on spine number and morphology, and that both DS brains and DS astrocytes exhibit marked deficits in TSP-1 protein expression. Depletion of TSP-1 from normal astrocytes resulted in dramatic changes in spine morphology, while restoration of TSP-1 levels prevented DS astrocyte-mediated spine and synaptic alterations. Astrocyte cultures derived from TSP-1 KO mice exhibited similar deficits to support spine formation and structure than DS astrocytes.Conclusions/SignificanceThese results indicate that human astrocytes promote spine and synapse formation, identify astrocyte dysfunction as a significant factor of spine and synaptic pathology in the DS brain, and provide a mechanistic rationale for the exploration of TSP-1-based therapies to treat spine and synaptic pathology in DS and other neurological conditions.

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The small GTPase Rac-1 is a regulator of mesangial cell morphology and thrombospondin-1 expression

Cited by 15 publications

References 54 publications

Inhibition of Egr1 expression underlies the anti-mitogenic effects of cAMP in vascular smooth muscle cells

Inhibition of Egr1 expression underlies the anti-mitogenic effects of cAMP in vascular smooth muscle cells

Pathophysiological Defects and Transcriptional Profiling in the RBM20-/- Rat Model

A Role for Thrombospondin-1 Deficits in Astrocyte-Mediated Spine and Synaptic Pathology in Down's Syndrome

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