Role of γ-Adducin in Actin Cytoskeleton Rearrangements in Podocyte Pathophysiology

We recently reported that the enhanced susceptibility to chronic kidney disease (CKD) in the FHH rat is caused, at least in part, by a mutation in γ-adducin (ADD3) that attenuates renal vascular function. The present study explored whether Add3 contributes to the modulation of podocyte structure and function using FHH and FHH.Add3 transgenic rats. The expression of ADD3 on the membrane of primary podocytes isolated from FHH was reduced compared with FHH.Add3 transgenic rats. We found that F-actin nets, which are typically localized in the lamellipodia, replaced unbranched stress fibers in conditionally immortalized mouse podocytes transfected with Add3 DsiRNA and primary podocytes isolated from FHH rats. There were increased F/G-actin ratio and expression of the Arp2/3 complexes throughout FHH podocytes in association with reduced synaptopodin and RhoA but enhanced Rac1 and CDC42 expression in the renal cortex, glomeruli and podocytes of FHH rats. The expression of Nephrin at the slit diaphragm and the levels of focal adhesion proteins ITGA3 and ITGB1 were decreased in the glomeruli of FHH rats. Cell migration was enhanced and adhesion was reduced in podocytes of FHH rats, as well as in immortalized mouse podocyte transfected with Add3 DsiRNA. Mean arterial pressures were similar in FHH and FHH.Add3 transgenic rats at 16-week of age; however, FHH rats exhibited enhanced proteinuria associated with podocyte foot process effacement. These results demonstrate that reduced ADD3 function in FHH rats alters baseline podocyte pathophysiology by rearrangement of the actin cytoskeleton at the onset of proteinuria in young animals.

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Novel role of Vav1-Rac1 pathway in actin cytoskeleton regulation in interleukin-13-induced minimal change-like nephropathy

Clinical Science ◽

10.1042/cs20160312 ◽

2016 ◽

Vol 130 (24) ◽

pp. 2317-2327 ◽

Cited By ~ 3

Author(s):

Chang-Yien Chan ◽

Kar-Hui Ng ◽

Jinmiao Chen ◽

Jinhua Lu ◽

Caroline Guat-Lay Lee ◽

...

Keyword(s):

Actin Cytoskeleton ◽

Rat Model ◽

Minimal Change ◽

Down Regulation ◽

Interleukin 13 ◽

Foot Process Effacement ◽

Foot Process ◽

Cytoskeleton Rearrangement

Podocyte foot process effacement and proteinuria seen in our interleukin-13 (IL-13) overexpression rat model of minimal change-like nephropathy was associated with marked down-regulation of podocyte-related genes and activation of Vav1-Rac1-induced actin cytoskeleton rearrangement in the podocytes.

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The role of Rho GTPases’ substrates Rac and Cdc42 in osteoclastogenesis and relevant natural medicinal products study

Bioscience Reports ◽

10.1042/bsr20200407 ◽

2020 ◽

Vol 40 (7) ◽

Author(s):

Yuan Liu ◽

Yusheng Dou ◽

Liang Yan ◽

Xiaobin Yang ◽

Baorong He ◽

...

Keyword(s):

Natural Products ◽

Drug Discovery ◽

Bone Loss ◽

Rho Gtpases ◽

Medicinal Products ◽

Cellular Functions ◽

Recent Advancement ◽

And Function ◽

Cytoskeleton Rearrangements

Abstract Recently, Rho GTPases substrates include Rac (Rac1 and Rac2) and Cdc42 that have been reported to exert multiple cellular functions in osteoclasts, the most prominent of which includes regulating the dynamic actin cytoskeleton rearrangements. In addition, natural products and their molecular frameworks have a long tradition as valuable starting points for medicinal chemistry and drug discovery. Although currently, there are reports about the natural product, which could play a therapeutic role in bone loss diseases (osteoporosis and osteolysis) through the regulation of Rac1/2 and Cdc42 during osteoclasts cytoskeletal structuring. There have been several excellent studies for exploring the therapeutic potentials of various natural products for their role in inhibiting cancer cells migration and function via regulating the Rac1/2 and Cdc42. Herein in this review, we try to focus on recent advancement studies for extensively understanding the role of Rho GTPases substrates Rac1, Rac2 and Cdc42 in osteoclastogenesis, as well as therapeutic potentials of natural medicinal products for their properties on the regulation of Rac1, and/or Rac2 and Cdc42, which is in order to inspire drug discovery in regulating osteoclastogenesis.

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Role of Actin Cytoskeleton in Dynamics and Function of the Serotonin1A Receptor

Biophysical Journal ◽

10.1016/j.bpj.2019.08.034 ◽

2020 ◽

Vol 118 (4) ◽

pp. 944-956

Author(s):

Sandeep Shrivastava ◽

Parijat Sarkar ◽

Pascal Preira ◽

Laurence Salomé ◽

Amitabha Chattopadhyay

Keyword(s):

Actin Cytoskeleton ◽

Serotonin1a Receptor ◽

Dynamics And Function ◽

And Function

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Abstract 348: Inhibition Of Phosphodiesterase 5 Attenuates Angiotensin II-dependent Hypertension And Renal Vascular Dysfunction In C57bl/6 Mice But Not In Enos-Ko Mice

Hypertension ◽

10.1161/hyp.64.suppl_1.348 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Manuel Thieme ◽

Sema Sivritas ◽

Sebastian A Potthoff ◽

Evanthia Mergia ◽

Lars C Rump ◽

...

Keyword(s):

Vascular Function ◽

Vascular Tone ◽

Vascular Dysfunction ◽

Pivotal Role ◽

Ang Ii ◽

Cgmp Signaling ◽

Renal Vascular ◽

The Impact

The kidney plays an outstanding role in the blood pressure (BP) regulation. The renal vasoconstrictor response to angiotensin (Ang) II is balanced by the NO/cGMP-signalling cascade. Ang II causes hypertension and vascular dysfunction by reducing cGMP sensitivity. Ang II is able to increase cGMP degradation by activating phosphodiesterase (PDE)1 and PDE5. The aim of the present study was to identify the predominant PDE subunit regulating renal blood flow (RBF) and vascular tone during hypertension. Therefore, we tested in vivo effects of acute PDE1 (vinpocetine) and PDE5 (sildenafil) inhibition at baseline and during acute Ang II infusion (200ng/kg/min). Furthermore, we examined the impact of PDE-inhibition on Ang II dependent hypertension (500ng/kg/min; 14 days) and on renal vascular function in the isolated perfused kidney. Acute vinpocetine administration (0.8-800μg/kg BW) showed almost no effect on systemic BP and RBF at baseline and during acute Ang II infusion. In contrast, sildenafil (0.8-800μg/kg BW) significantly decreased BP under baseline conditions. During acute Ang II infusion, BP reduction and RBF increase induced by sildenafil was even more pronounced suggesting a pivotal role of the PDE5 in the regulation of renal vascular tone. Based on these results, we tested whether inhibition of the PDE5 protects from hypertension and vascular dysfunction. Indeed, chronic sildenafil treatment significantly attenuated Ang II dependent hypertension in C57BL/6 (vehicle vs. sil: 156±4 vs. 139±7; p<0.05). Moreover, Sildenafil treatment significantly improved NO-dependent vasorelaxation in kidneys of Ang II- treated C57BL/6. To confirm that PDE5 is activated by an increased NO/cGMP signaling, we used eNOS-KO mice, a model known for decreased NO dependent cGMP generation. In eNOS-KO mice, sildenafil failed to reduce Ang II dependent hypertension (172,4 ± 4,3 mmHg vs. 166,1 ± 3,8 mmHg, p=0,2753) and did not improve vascular dysfunction in Ang II treated kidneys. In summary, the PDE5 is the predominant PDE regulating RBF. Inhibition of PDE5 by sildenafil ameliorates chronic Ang II dependent hypertension and improves vascular dysfunction. This study reveals new evidence for the pivotal role of PDE5 in the pathogenesis of AngII-induced hypertension.

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Schip1 Is a Novel Podocyte Foot Process Protein that Mediates Actin Cytoskeleton Rearrangements and Forms a Complex with Nherf2 and Ezrin

PLoS ONE ◽

10.1371/journal.pone.0122067 ◽

2015 ◽

Vol 10 (3) ◽

pp. e0122067 ◽

Cited By ~ 10

Author(s):

Ljubica Perisic ◽

Patricia Q. Rodriguez ◽

Kjell Hultenby ◽

Ying Sun ◽

Mark Lal ◽

...

Keyword(s):

Actin Cytoskeleton ◽

Foot Process ◽

Cytoskeleton Rearrangements

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Role of the Rho-ROCK (Rho-Associated Kinase) Signaling Pathway in the Regulation of Pancreatic β-Cell Function

Endocrinology ◽

10.1210/en.2008-1135 ◽

2008 ◽

Vol 150 (5) ◽

pp. 2072-2079 ◽

Cited By ~ 31

Author(s):

Eva Hammar ◽

Alejandra Tomas ◽

Domenico Bosco ◽

Philippe A. Halban

Keyword(s):

Extracellular Matrix ◽

Insulin Secretion ◽

Actin Cytoskeleton ◽

Cell Function ◽

Pancreatic Β Cell ◽

Β Cell ◽

Β Cell Function ◽

Glucose Stimulated Insulin Secretion ◽

And Function

Extracellular matrix has a beneficial impact on β-cell spreading and function, but the underlying signaling pathways have yet to be fully elucidated. In other cell types, Rho, a well-characterized member of the family of Rho GTPases, and its effector Rho-associated kinase (ROCK), play an important role as downstream mediators of outside in signaling from extracellular matrix. Therefore, a possible role of the Rho-ROCK pathway in β-cell spreading, actin cytoskeleton dynamics, and function was investigated. Rho was inhibited using a new cell-permeable version of C3 transferase, whereas the activity of ROCK was repressed using the specific ROCK inhibitors H-1152 and Y-27632. Inhibition of Rho and of ROCK increased spreading and improved both short-term and prolonged glucose-stimulated insulin secretion but had no impact on basal secretion. Inhibition of this pathway led to a depolymerization of the actin cytoskeleton. Furthermore, the impact of the inhibition of ROCK on stimulated insulin secretion was acute and reversible, suggesting that rapid signaling such as phosphorylation is involved. Finally, quantification of the activity of RhoA indicated that the extracellular matrix represses RhoA activity. Overall these results show for the first time that the Rho-ROCK signaling pathway contributes to the stabilization of the actin cytoskeleton and inhibits glucose-stimulated insulin secretion in primary pancreatic β-cells. Furthermore, they indicate that inhibition of this pathway might be one of the mechanisms by which the extracellular matrix exerts its beneficial effects on pancreatic β-cell function.

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The Role of Nod Factor Substituents in Actin Cytoskeleton Rearrangements in Phaseolus vulgaris

Molecular Plant-Microbe Interactions ◽

10.1094/mpmi.2003.16.4.326 ◽

2003 ◽

Vol 16 (4) ◽

pp. 326-334 ◽

Cited By ~ 25

Author(s):

Luis Cárdenas ◽

Jane E. Thomas-Oates ◽

Noreide Nava ◽

Isabel M. López-Lara ◽

Peter K. Hepler ◽

...

Keyword(s):

Actin Cytoskeleton ◽

Root Hair ◽

Terminal Residue ◽

Root Hair Cell ◽

Acetyl Group ◽

Cytoskeletal Rearrangements ◽

Cytoskeleton Rearrangements ◽

Hair Curling ◽

Root Hair Curling

In order to define the symbiotic role of some of the chemical substituents in the Rhizobium etli Nod factors (NFs), we purified Nod metabolites secreted by the SM25 strain, which carries most of the nodulation genes, and SM17 with an insertion in nodS. These NFs were analyzed for their capabilities to induce root hair curling and cytoskeletal rearrangements. The NFs secreted by strain SM17 lack the carbamoyl and methyl substituents on the nonreducing terminal residue and an acetyl moiety on the fucosyl residue on the reducing-terminal residue as determined by mass spectrometry. We have reported previously that the root hair cell actin cytoskeleton from bean responds with a rapid fragmentation of the actin bundles within 5 min of NF exposure, and also is accompanied by increases in the apical influxes and intracellular calcium levels. In this article, we report that methyl-bearing NFs are more active in inducing root hair curling and actin cytoskeleton rearrangements than nonmethylated NFs. However, the carbamoyl residue on the nonreducing terminal residue and the acetyl group at the fucosyl residue on the reducing terminal residue do not seem to have any effect on root hair curling induction or in actin cytoskeleton rearrangement.

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The Significant Role of the Microfilament System in Tumors

Frontiers in Oncology ◽

10.3389/fonc.2021.620390 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xin Jiang ◽

Yiming Qin ◽

Liu Kun ◽

Yanhong Zhou

Keyword(s):

Actin Cytoskeleton ◽

Cell Movement ◽

Structural Protein ◽

Tissue Integrity ◽

Basic Functions ◽

Treatment Research ◽

Target Molecules ◽

Microfilament System ◽

And Function

Actin is the structural protein of microfilaments, and it usually exists in two forms: monomer and polymer. Among them, monomer actin is a spherical molecule composed of a polypeptide chain, also known as spherical actin. The function of actin polymers is to produce actin filaments, so it is also called fibroactin. The actin cytoskeleton is considered to be an important subcellular filament system. It interacts with numerous relevant proteins and regulatory cells, regulating basic functions, from cell division and muscle contraction to cell movement and ensuring tissue integrity. The dynamic reorganization of the actin cytoskeleton has immense influence on the progression and metastasis of cancer as well. This paper explores the significance of the microfilament network, the dynamic changes of its structure and function in the presence of a tumor, the formation process around the actin system, and the relevant proteins that may be target molecules for anticancer drugs so as to provide support and reference for interlinked cancer treatment research in the future.

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Endothelial Aldehyde Dehydrogenase 2 as a Target to Maintain Vascular Wellness and Function in Ageing

Biomedicines ◽

10.3390/biomedicines8010004 ◽

2020 ◽

Vol 8 (1) ◽

pp. 4 ◽

Cited By ~ 2

Author(s):

Ginevra Nannelli ◽

Marina Ziche ◽

Sandra Donnini ◽

Lucia Morbidelli

Keyword(s):

Aldehyde Dehydrogenase ◽

Vascular Function ◽

Vascular Dysfunction ◽

Low Grade ◽

Loss Of Function ◽

Aldehyde Dehydrogenase 2 ◽

Main Determinants ◽

And Function ◽

Low Grade Inflammation

Endothelial cells are the main determinants of vascular function, since their dysfunction in response to a series of cardiovascular risk factors is responsible for disease progression and further consequences. Endothelial dysfunction, if not resolved, further aggravates the oxidative status and vessel wall inflammation, thus igniting a vicious cycle. We have furthermore to consider the physiological manifestation of vascular dysfunction and chronic low-grade inflammation during ageing, also known as inflammageing. Based on these considerations, knowledge of the molecular mechanism(s) responsible for endothelial loss-of-function can be pivotal to identify novel targets of intervention with the aim of maintaining endothelial wellness and vessel trophism and function. In this review we have examined the role of the detoxifying enzyme aldehyde dehydrogenase 2 (ALDH2) in the maintenance of endothelial function. Its impairment indeed is associated with oxidative stress and ageing, and in the development of atherosclerosis and neurodegenerative diseases. Strategies to improve its expression and activity may be beneficial in these largely diffused disorders.

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