scholarly journals The NF-κB essential modulator (NEMO) controls podocyte cytoskeletal dynamics independently of NF-κB

2015 ◽  
Vol 309 (7) ◽  
pp. F617-F626 ◽  
Author(s):  
Sebastian Brähler ◽  
Christina Ising ◽  
Belén Barrera Aranda ◽  
Martin Höhne ◽  
Bernhard Schermer ◽  
...  
Keyword(s):  
Map Kinases ◽  
Small Gtpases ◽  
Migratory Response ◽  
Filtration Barrier ◽  
Tnf Α ◽  
Cytoskeletal Dynamics ◽  
Fenestrated Endothelium ◽  
End Stage ◽  
Cytoskeletal Rearrangements

Maintenance of the glomerular filtration barrier with its fenestrated endothelium, the glomerular basement membrane, and the podocytes as the outer layer, is a major prerequisite for proper renal function. Tight regulation of the balance between plasticity and rigidity of the podocytes' architecture is required to prevent the onset of glomerular disease, mainly proteinuria. The underlying cellular signaling pathways that regulate the organization of the podocytes' cytoskeleton are still a matter of controversial debate. In this study, we investigated the role of the NF-κB signaling pathway in podocyte cytoskeletal dynamics. As previously published, genetic inhibition of the NF-κB essential modulator (NEMO) in podocytes does not affect glomerular function under physiological, nonstressed conditions nor does it alter the initial podocyte response in an experimental glomerulonephritis (NTN) model (Brähler S, Ising C, Hagmann H, Rasmus M, Hoehne M, Kurschat C, Kisner T, Goebel H, Shankland SJ, Addicks K, Thaiss F, Schermer B, Pasparakis M, Benzing T, Brinkkoetter PT. Am J Physiol Renal Physiol 303: F1473–F1475, 2012). Quite the contrary, podocyte-specific NEMO null mice recovered significantly faster and did not develop glomerulosclerosis and end-stage renal failure over time. Here, we show that cytoskeletal rearrangements and increased podocyte motility following stimulation with IL-1, TNF-α, or LPS depend on NEMO. NEMO also regulates the phosphorylation of the MAP kinase ERK1/2 and suppresses the activation of RhoA following stimulation with IL-1. The migratory response and altered ERK1/2 phosphorylation is independent of NF-κB signaling as demonstrated by expression of a mutant IκB resistant to phosphorylation and degradation. In conclusion, signaling through NEMO might not only be involved in the production of NF-κB proinflammatory chemokines but also regulates podocyte dynamics independently of NF-κB, most likely through small GTPases and MAP kinases.

scholarly journals Inherited podocytopathies

2008 ◽  
Vol 136 (Suppl. 4) ◽  
pp. 327-339
Author(s):  
Radovan Bogdanovic
Keyword(s):  
Congenital Nephrotic Syndrome ◽  
Structural Studies ◽  
Glomerular Filtration Barrier ◽  
Filtration Barrier ◽  
Glomerular Epithelial Cells ◽  
Causes Of Disease ◽  
Stage Renal Disease ◽  
End Stage ◽  
Made In

Podocytes, the visceral glomerular epithelial cells, are the postmythotic cells that line the outer aspects of the glomerular basement membrane. A number of advances have been made in recent years, linked to the discovery of singlegene defects in hereditary glomerular disease, which highlight the role of these cells in preventing proteinuria. Despite the rarity of hereditary proteinuric syndromes, genetic, biochemical, and structural studies of these diseases have made important contributions to our knowledge of how the normal glomerular filter works and the mechanism of proteinuria. The course of these diseases can vary; some patients present with severe proteinuria and congenital nephrotic syndrome, whereas others have only moderate proteinuria and focal segmental glomerulosclerosis. Regardless of its cause, the disease often progresses to end-stage renal disease. There can be overlap between the diseases: mutations in the same gene can lead to different renal phenotypes. It is important to know that some hereditary podocytopathies respond to therapy, whereas majority does not. For this reason, genetic testing, which is available for some hereditary podocytopathies should be performed whenever possible. This review summarizes recent progress in the eludication of genetic causes of disease and discusses their implication for the understanding of the pathogenic mechanisms which can lead to disruption of the glomerular filtration barrier.

scholarly journals Arp2/3-Branched Actin Maintains an Active Pool of GTP-RhoA and Controls RhoA Abundance

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1264
Author(s):  
Yuxing Huang ◽  
Xin Yi ◽  
Chenlu Kang ◽  
Congying Wu
Keyword(s):  
Signal Transduction ◽  
Cell Motility ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Protein Abundance ◽  
Rhoa Activity ◽  
Cytoskeletal Dynamics ◽  
Active Pool ◽  
Spatiotemporal Control

Small GTPases regulate cytoskeletal dynamics, cell motility, and division under precise spatiotemporal control. Different small GTPases exhibit cross talks to exert feedback response or to act in concert during signal transduction. However, whether and how specific cytoskeletal components’ feedback to upstream signaling factors remains largely elusive. Here, we report an intriguing finding that disruption of the Arp2/3-branched actin specifically reduces RhoA activity but upregulates its total protein abundance. We further dissect the mechanisms underlying these circumstances and identify the altered cortactin/p190RhoGAP interaction and weakened CCM2/Smurf1 binding to be involved in GTP-RhoA reduction and total RhoA increase, respectively. Moreover, we find that cytokinesis defects induced by Arp2/3 inhibition can be rescued by activating RhoA. Our study reveals an intricate feedback from the actin cytoskeleton to the small GTPase. Our work highlights the role of Arp2/3-branched actin in signal transduction aside from its function in serving as critical cytoskeletal components to maintain cell morphology and motility.

scholarly journals Joining forces: crosstalk between biochemical signalling and physical forces orchestrates cellular polarity and dynamics

2018 ◽  
Vol 373 (1747) ◽  
pp. 20170145 ◽  
Author(s):  
Suvrajit Saha ◽  
Tamas L. Nagy ◽  
Orion D. Weiner
Keyword(s):  
Cell Biology ◽  
Cell Movement ◽  
Special Focus ◽  
Cellular Motility ◽  
Cellular Polarity ◽  
Self Organized ◽  
Cytoskeletal Dynamics ◽  
Physical Forces ◽  
Cytoskeletal Rearrangements

Dynamic processes like cell migration and morphogenesis emerge from the self-organized interaction between signalling and cytoskeletal rearrangements. How are these molecular to sub-cellular scale processes integrated to enable cell-wide responses? A growing body of recent studies suggest that forces generated by cytoskeletal dynamics and motor activity at the cellular or tissue scale can organize processes ranging from cell movement, polarity and division to the coordination of responses across fields of cells. To do so, forces not only act mechanically but also engage with biochemical signalling. Here, we review recent advances in our understanding of this dynamic crosstalk between biochemical signalling, self-organized cortical actomyosin dynamics and physical forces with a special focus on the role of membrane tension in integrating cellular motility. This article is part of the theme issue ‘Self-organization in cell biology’.

Lipopolysaccharide and proinflammatory cytokines stimulate interleukin-6 expression in C2C12 myoblasts: role of the Jun NH2-terminal kinase

2003 ◽  
Vol 285 (5) ◽  
pp. R1153-R1164 ◽  
Author(s):  
Robert A. Frost ◽  
Gerald J. Nystrom ◽  
Charles H. Lang
Keyword(s):  
Skeletal Muscle ◽  
Map Kinases ◽  
Kinase Inhibitors ◽  
Inhibitory Effect ◽  
C2c12 Myoblasts ◽  
Downstream Target ◽  
Tnf Α ◽  
Inflammatory Stimuli

IL-6 is a major inflammatory cytokine that plays a central role in coordinating the acute-phase response to trauma, injury, and infection in vivo. Although IL-6 is synthesized predominantly by macrophages and lymphocytes, skeletal muscle is a newly recognized source of this cytokine. IL-6 from muscle spills into the circulation, and blood-borne IL-6 can be elevated >100-fold due to exercise and injury. The purpose of the present study was to determine whether inflammatory stimuli, such as LPS, TNF-α, and IL-1β, could increase IL-6 expression in skeletal muscle and C2C12 myoblasts. Second, we investigated the role of mitogen-activated protein (MAP) kinases, and the Jun NH2-terminal kinase (JNK) in particular, as a mediator of this response. Intraperitoneal injection of LPS in mice increased the circulating concentration of IL-6 from undetectable levels to 4 ng/ml. LPS also increased IL-6 mRNA 100-fold in mouse fast-twitch skeletal muscle. Addition of LPS, IL-1β, or TNF-α directly to C2C12 myoblasts increased IL-6 protein (6- to 8-fold) and IL-6 mRNA (5- to 10-fold). The response to all three stimuli was completely blocked by the JNK inhibitor SP-600125 but not as effectively by other MAP kinase inhibitors. SP-600125 blocked LPS-stimulated IL-6 synthesis dose dependently at both the RNA and protein level. SP-600125 was as effective as the synthetic glucocorticoid dexamethasone at inhibiting IL-6 expression. SP-600125 inhibited IL-6 synthesis when added to cells up to 60 min after LPS stimulation, but its inhibitory effect waned with time. LPS stimulated IL-6 mRNA in both myoblasts and myotubes, but myoblasts showed a proportionally greater LPS-induced increase in IL-6 protein expression compared with myotubes. SP-600125 and the proteasomal inhibitor MG-132 blocked LPS-induced degradation of IκB-α/ϵ and LPS-stimulated expression of IκB-α mRNA. Yet, only SP-600125 and not MG-132 blocked LPS-induced IL-6 mRNA expression. This suggests that IL-6 gene expression is a downstream target of JNK in C2C12 myoblasts.

scholarly journals Nicotine, Smoking, Podocytes and Diabetic Nephropathy

2021 ◽  
Author(s):  
Edgar A. Jaimes ◽  
Ming-Sheng Zhou ◽  
Mohammed Siddiqui ◽  
Gabriel Rezonzew ◽  
Runxia Tian ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Electronic Cigarettes ◽  
Pressure Control ◽  
Lipid Uptake ◽  
Novel Studies ◽  
Filtration Barrier ◽  
Fibronectin Expression ◽  
End Stage ◽  
And Function

Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. Besides glycemic and blood pressure control, environmental factors such as cigarette smoking (CS) adversely affect the progression of DN. The effects of CS on DN progression have been attributed to combustion generated molecules without consideration to the role of nicotine (NIC), responsible for the addictive properties of both CS and electronic cigarettes (EC). Podocytes (POD) are essential to preserve the structure and function of the glomerular filtration barrier and strong evidence indicates that early POD loss promotes DN progression. We performed studies in human POD and in a mouse model of diabetes that develops nephropathy resembling human DN. We determined that NIC binding to podocytes in concentrations achieved with CS and EC activated NADPH oxidase, which sets in motion a dysfunctional molecular network integrated by COX2, known to induce podocyte injury; downregulation of AMPK, important for maintaining cellular energy stores and antioxidation and upregulation of CD36 that increased lipid uptake and promoted apoptosis. In diabetic mice NIC increased proteinuria, a recognized marker of CKD progression, accompanied by reduced glomerular podocyte synaptopodin, a crucial stabilizer of POD cytoskeleton and increased fibronectin expression. These novel studies critically implicate NIC itself as a contributor to DN progression in CS and EC users.

scholarly journals Small GTPases and Their Role in Vascular Disease

2019 ◽  
Vol 20 (4) ◽  
pp. 917 ◽  
Author(s):  
Alison Flentje ◽  
Richa Kalsi ◽  
Thomas Monahan
Keyword(s):  
Cardiovascular Disease ◽  
Endothelial Cells ◽  
Blood Vessel ◽  
Vascular Disease ◽  
The United States ◽  
Small Gtpases ◽  
Endothelial Cell Migration ◽  
Open Reconstruction ◽  
End Stage

Over eighty million people in the United States have cardiovascular disease that can affect the heart causing myocardial infarction; the carotid arteries causing stroke; and the lower extremities leading to amputation. The treatment for end-stage cardiovascular disease is surgical—either endovascular therapy with balloons and stents—or open reconstruction to reestablish blood flow. All interventions damage or destroy the protective inner lining of the blood vessel—the endothelium. An intact endothelium is essential to provide a protective; antithrombotic lining of a blood vessel. Currently; there are no agents used in the clinical setting that promote reendothelialization. This process requires migration of endothelial cells to the denuded vessel; proliferation of endothelial cells on the denuded vessel surface; and the reconstitution of the tight adherence junctions responsible for the formation of an impermeable surface. These processes are all regulated in part and are dependent on small GTPases. As important as the small GTPases are for reendothelialization, dysregulation of these molecules can result in various vascular pathologies including aneurysm formation, atherosclerosis, diabetes, angiogenesis, and hypertension. A better understanding of the role of small GTPases in endothelial cell migration is essential to the development for novel agents to treat vascular disease.

GRO-α regulation in airway smooth muscle by IL-1β and TNF-α: role of NF-κB and MAP kinases

2006 ◽  
Vol 291 (1) ◽  
pp. L66-L74 ◽  
Author(s):  
Razao Issa ◽  
Shaoping Xie ◽  
Kang-Yun Lee ◽  
Rex D. Stanbridge ◽  
Pankaj Bhavsar ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Mrna Expression ◽  
Airway Smooth Muscle ◽  
Map Kinases ◽  
Inflammatory Responses ◽  
Airway Smooth Muscle Cells ◽  
Dependent Manner ◽  
Tnf Α ◽  
Inflammatory Chemokines

Airway smooth muscle cells (ASMC) are a source of inflammatory chemokines that may propagate airway inflammatory responses. We investigated the production of the CXC chemokine growth-related oncogene protein-α (GRO-α) from ASMC induced by cytokines and the role of MAPK and NF-κB pathways. ASMC were cultured from human airways, grown to confluence, and exposed to cytokines IL-1β and TNF-α after growth arrest. GRO-α release, measured by ELISA, was increased by >50-fold after IL-1β (0.1 ng/ml) or 5-fold after TNF-α (1 ng/ml) in a dose- and time-dependent manner. GRO-α release was not affected by the T helper type 2 cytokines IL-4, IL-10, and IL-13. IL-1β and TNF-α also induced GRO-α mRNA expression. Supernatants from IL-1β-stimulated ASMC were chemotactic for neutrophils; this effect was inhibited by anti-GRO-α blocking antibody. AS-602868, an inhibitor of IKK-2, and PD-98059, an inhibitor of ERK, inhibited GRO-α release and mRNA expression, whereas SP-600125, an inhibitor of JNK, reduced GRO-α release without effect on mRNA expression. SB-203580, an inhibitor of p38 MAPK, had no effect. AS-602868 but not PD-98059 or SP-600125 inhibited p65 DNA-binding induced by IL-1β and TNF-α. By chromatin immunoprecipitation assay, IL-1β and TNF-α enhanced p65 binding to the GRO-α promoter, which was inhibited by AS-602868. IL-1β- and TNF-α-stimulated expression of GRO-α from ASMC is regulated by independent pathways involving NF-κB activation and ERK and JNK pathways. GRO-α released from ASMC participates in neutrophil chemotaxis.

scholarly journals CRL5-dependent regulation of the small GTPases ARL4C and ARF6 controls hippocampal morphogenesis

2020 ◽  
Vol 117 (37) ◽  
pp. 23073-23084
Author(s):  
Jisoo S. Han ◽  
Keiko Hino ◽  
Wenzhe Li ◽  
Raenier V. Reyes ◽  
Cesar P. Canales ◽  
...  
Keyword(s):  
Pyramidal Neuron ◽  
Pyramidal Neurons ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Cullin 5 ◽  
Hippocampal Development ◽  
The Stability ◽  
Cytoskeletal Rearrangements ◽  
Apical Dendrites

The small GTPase ARL4C participates in the regulation of cell migration, cytoskeletal rearrangements, and vesicular trafficking in epithelial cells. The ARL4C signaling cascade starts by the recruitment of the ARF–GEF cytohesins to the plasma membrane, which, in turn, bind and activate the small GTPase ARF6. However, the role of ARL4C–cytohesin–ARF6 signaling during hippocampal development remains elusive. Here, we report that the E3 ubiquitin ligase Cullin 5/RBX2 (CRL5) controls the stability of ARL4C and its signaling effectors to regulate hippocampal morphogenesis. Both RBX2 knockout and Cullin 5 knockdown cause hippocampal pyramidal neuron mislocalization and development of multiple apical dendrites. We used quantitative mass spectrometry to show that ARL4C, Cytohesin-1/3, and ARF6 accumulate in the RBX2 mutant telencephalon. Furthermore, we show that depletion of ARL4C rescues the phenotypes caused by Cullin 5 knockdown, whereas depletion of CYTH1 or ARF6 exacerbates overmigration. Finally, we show that ARL4C, CYTH1, and ARF6 are necessary for the dendritic outgrowth of pyramidal neurons to the superficial strata of the hippocampus. Overall, we identified CRL5 as a key regulator of hippocampal development and uncovered ARL4C, CYTH1, and ARF6 as CRL5-regulated signaling effectors that control pyramidal neuron migration and dendritogenesis.

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