F-actin fiber distribution in glomerular cells: Structural and functional implications

Cortés, Pedro; Méndez, Mariela; Riser, Bruce L.; Guérin, Christopher J.; Rodríguez-Barbero, Alicia; Hassett, Clare; Yee, Jerry

doi:10.1046/j.1523-1755.2000.00428.x

Cited by 75 publications

(67 citation statements)

References 32 publications

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“…This interpretation of the in vivo findings is consistent with our results in vitro, which show that mesangial cells, an important target for mechanically induced glomerular injury, 37 when subjected to mechanical stretch, upregulate GLUT-1 protein expression as well as basal glucose transport through a TGF-␤ 1 -dependent mechanism.…”

Section: Discussionsupporting

confidence: 92%

GLUT-1 Overexpression

et al. 2003

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Abstract-Mesangial matrix deposition is the hallmark of hypertensive and diabetic glomerulopathy. At similar levels of systemic hypertension, Dahl salt-sensitive but not spontaneously hypertensive rats (SHR) develop glomerular hypertension, which is accompanied by upregulation of transforming growth factor ␤ 1 (TGF-␤ 1 ), mesangial matrix expansion, and sclerosis. GLUT-1 is ubiquitously expressed and is the predominant glucose transporter in mesangial cells. In mesangial cells in vitro, GLUT-1 overexpression increases basal glucose transport, resulting in excess fibronectin and collagen production.

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Section: Discussionsupporting

confidence: 92%

GLUT-1 Overexpression

et al. 2003

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“…Particularly interesting was the enhanced expression of two genes, namely profilin and ARP-3, which encode proteins involved in key regulatory pathways of actin cytoskeletal turnover (32). In light of our identifying a cohort of actin cytoskeletal regulatory protein genes as being induced in our model system of DN, it is interesting that cytoskeletal alteration is postulated to be a contributor to glomerulosclerosis (20). A general potential link between development of glomerulosclerosis and alterations in the actin cytoskeleton is further strengthened by a recent report linking ␣-actinin-4 function with focal and segmental glomerulosclerosis (33).…”

Section: Ssh Identified a Series Of Mesangial Cell Genes Differentialmentioning

confidence: 96%

“…The differential expression of this functional class in response to glucose was noteworthy given the roles played by several of these actin cytoskeleton regulatory proteins in the growth and dissolution of actin filaments. In addition, increasing evidence indicates that cytoskeletal disassembly contributes to the mesangial cell and vascular smooth muscle cell hyporesponsiveness to vasopressors in models of DN both in vitro and in vivo (20,21). ADP-ribosylation factor GTPase-activating Protein (ASAP1) is an actin cytoskeletal regulatory protein identified here as being up-regulated in response to high glucose.…”

Section: Ssh Identified a Series Of Mesangial Cell Genes Differentialmentioning

confidence: 99%

High Glucose-altered Gene Expression in Mesangial Cells

Clarkson¹,

Murphy²,

Gupta³

et al. 2002

Journal of Biological Chemistry

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High extracellular glucose plays a pivotal role in the pathophysiology of diabetic nephropathy. Here we report 200 genes, identified using suppression-subtractive hybridization, that are differentially expressed when human mesangial cells are propagated in high ambient glucose in vitro. The major functional classes of genes identified included modulators and products of extracellular matrix protein metabolism, regulators of cell growth and turnover, and a cohort of actin cytoskeleton regulatory proteins. Actin cytoskeletal disassembly is a prominent feature of diabetic nephropathy. The induction of actin cytoskeleton regulatory gene expression by high glucose was attenuated by the inhibitor of reactive oxygen species generation, carbonyl cyanide m-chlorophenylhydrazone but not by the protein kinase C inhibitor GF 109203X and was not mimicked by the addition of transforming growth factor ␤. Enhanced expression of actin cytoskeleton regulatory genes was also observed following disruption of the mesangial cell actin cytoskeleton by cytochalasin D. In aggregate, these results suggest that the induction of genes encoding actin cytoskeleton regulatory proteins (a) is a prominent component of the mesangial cell transcriptomic response in diabetic nephropathy and (b) is dependent on oxidative stress, is independent of protein kinase C and transforming growth factor-␤, and represents an adaptive response to actin cytoskeleton disassembly. Diabetic nephropathy (DN)1 accounts for over one-third of all new cases of end stage renal failure in Western society (1).Glomerulosclerosis is the pathological hallmark of DN and reflects, in large part, altered mesangial cell matrix metabolism (2-6). The latter is triggered, in turn, by the complex interplay of metabolic and hemodynamic stress (2-6). Putative mediators of high glucose-induced mesangial cell dysfunction include oxidative stress, glomerular hypertension, protein kinase C (PKC) activation, transforming growth factor (TGF-␤), cell sorbitol accumulation, and advanced glycosylation end products (2-7). The molecular components of the mesangial cell response to high glucose stress are still being defined. With the completion of the human genome project, the monitoring of changes in the cellular transcriptome in response to diseasemimicking stimuli provides a powerful methodology for dissecting the molecular basis of disease. Here we employed a PCRbased technique, namely suppression-subtractive hybridization (SSH), to assess the influence of high extracellular glucose on gene expression by cultured human mesangial cells. This technique has the advantage over most other PCR-based techniques, such as differential display PCR, of including a normalization step that removes bias for the more abundant cellular transcripts. SSH may be more sensitive than most currently available oligonucleotide microarray systems, being able to detect relatively small changes in gene expression down to 1.5-fold as judged by Northern blot analysis. SSH identified some 200 genes that are differentiall...

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“…This absence of change in the mesangial vimentin network has been already described in pathologic models that cause actin fiber disorganization, such as the diabetic glomerulus. 1 MLC phosphorylation is another critical step in the formation of actin stress fibers and the induction of cell migration and is the essential factor that determines the extent to which smooth muscle and nonmuscle cells contract, because it regulates the Mg-ATPase activity of myosin type II. 14,22 Addition of angiotensin II to the culture medium induced a rapid (within 10 minutes) increase in the amount of both mono-and di-phosphorylated MLC.…”

Section: Dubus Et Al Mesangial Cell Motility and Mycophenolic Acidmentioning

confidence: 99%

“…Upregulation of numerous cytoskeletal proteins, particularly ␣-smooth muscle actin (SMA), has been identified as a marker of mesangial activation that occurs during repopulation of the glomerulus after glomerular injury. 1 Isolation and culture of human mesangial cells cause profound changes in cellular morphology similar to that seen during in vivo activation: increased cell flattening and adhesion, with elaboration of filopodia and lamellipodia structures that are sites of cytoplasmic growth and movement.…”

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confidence: 99%

Cytoskeletal Reorganization by Mycophenolic Acid Alters Mesangial Cell Migration and Contractility

et al. 2003

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Abstract-Cytoskeleton alterations are a hallmark of mesangial cell activation during glomerulosclerosis. The aim of this study was to investigate whether mycophenolic acid (MPA) affects cytoskeletal organization and motility of human mesangial cells. Using the IP15 cell line, we found that treatment with 1 mol/L MPA inhibited both receptor-dependent (angiotensin II) and receptor-independent (KCl) contractile responses, as well as serum-induced migration activity, suggesting alterations in the intracellular mechanisms that control mesangial cell motility. Immunofluorescence studies of MPA-treated cells provided evidence for decreased membrane disassembly/reassembly of ␣-smooth muscle actin and F-actin fibers, which was correlated with sustained quantitative and qualitative modifications of actin-associated proteins: calponin was overexpressed and became associated with actin fibers, whereas phosphorylation levels of cofilin and myosin light chain increased, suggesting both an activation of the mechanisms responsible for actin polymerization and an inhibition of actin-depolymerizing processes. These observations support a stabilizing effect of MPA on the mesangial actin cytoskeleton, which constitutes an additive action by which MPA, beyond its anti-inflammatory, antiproliferative and antifibrotic properties, might protect against excessive mesangial activation in the context of various glomerulopathies and kidney transplantation.

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F-actin fiber distribution in glomerular cells: Structural and functional implications

Cited by 75 publications

References 32 publications

GLUT-1 Overexpression

GLUT-1 Overexpression

High Glucose-altered Gene Expression in Mesangial Cells

Cytoskeletal Reorganization by Mycophenolic Acid Alters Mesangial Cell Migration and Contractility

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