Complement-mediated injury reversibly disrupts glomerular epithelial cell actin microfilaments and focal adhesions

Topham, Peter; Haydar, Samir; Kuphal, Roy; Lightfoot, Jeffrey; Salant, David J.

doi:10.1046/j.1523-1755.1999.00407.x

Cited by 78 publications

(57 citation statements)

References 23 publications

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“…This is accompanied by various alterations in the intervening filtration slits, including widening, formation of occluding-type junctions, and displacement and disruption of slit-diaphragms (31,122). In an in vitro model of anti-Fx1A-and complement-mediated sublethal injury of rat GEC, C5b-9 assembly induced the dissolution of F-actin microfilaments and loss of the focal adhesion complexes that anchor the cytoskeleton to integrins (139). The in vitro changes were found to be reversible as the cells recovered when the antibodies and complement were removed (139).…”

Section: Podocyte Cytoskeletal Changes Induced By Antibody and Complementioning

confidence: 98%

“…In an in vitro model of anti-Fx1A-and complement-mediated sublethal injury of rat GEC, C5b-9 assembly induced the dissolution of F-actin microfilaments and loss of the focal adhesion complexes that anchor the cytoskeleton to integrins (139). The in vitro changes were found to be reversible as the cells recovered when the antibodies and complement were removed (139). The disassembly of focal adhesions was associated with substantial ATP depletion and dephosphorylation of paxillin and other proteins but was not prevented by tyrosine phosphatase inhibition, nor was reassembly retarded by tyrosine kinase inhibition.…”

Section: Podocyte Cytoskeletal Changes Induced By Antibody and Complementioning

confidence: 99%

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Experimental membranous nephropathy redux

Cybulsky

Quigg²,

Salant³

2005

American Journal of Physiology-Renal Physiology

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115

133

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Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. Active and passive Heymann nephritis (HN) in rats are valuable experimental models because their features so closely resemble human MN. In HN, subepithelial immune deposits form in situ as a result of circulating antibodies. Complement activation leads to assembly of C5b-9 on glomerular epithelial cell (GEC) plasma membranes and is essential for sublethal GEC injury and the onset of proteinuria. This review revisits HN and focuses on areas of substantial progress in recent years. The response of the GEC to sublethal C5b-9 attack is not simply due to disruption of the plasma membrane but is due to the activation of specific signaling pathways. These include activation of protein kinases, phospholipases, cyclooxygenases, transcription factors, growth factors, NADPH oxidase, stress proteins, proteinases, and others. Ultimately, these signals impact on cell metabolic pathways and the structure/function of lipids and key proteins in the cytoskeleton and slit-diaphragm. Some signals affect GEC adversely. Thus C5b-9 induces partial dissolution of the actin cytoskeleton. There is a decline in nephrin expression, reduction in F-actin-bound nephrin, and loss of slit-diaphragm integrity. Other signals, such as endoplasmic reticulum stress, may limit complement-induced injury, or promote recovery. The extent of complement activation and GEC injury is dependent, in part, on complement-regulatory proteins, which act at early or late steps within the complement cascade. Identification of key steps in complement activation, the cellular signaling pathways, and the targets will facilitate therapeutic intervention in reversing GEC injury in human MN.

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Section: Podocyte Cytoskeletal Changes Induced By Antibody and Complementioning

confidence: 98%

Section: Podocyte Cytoskeletal Changes Induced By Antibody and Complementioning

confidence: 99%

Experimental membranous nephropathy redux

Cybulsky

Quigg²,

Salant³

2005

American Journal of Physiology-Renal Physiology

Self Cite

115

133

View full text Add to dashboard Cite

show abstract

“…The mammalian unfolded protein response, although analogous to yeast, is more complex and appears to involve additional pathways and effectors (46). C5b-9-induced sublethal cell injury may lead to a decline in cellular ATP, mitochondrial lipid perturbation, or loss of mitochondrial membrane potential (47)(48)(49), whereas at high doses, C5b-9 can induce mitochondrial damage and cell necrosis (50). Based on biochemical and morphologic observations (36,49), it is likely that, during complement-dependent GEC injury, integral membrane and secretory proteins are altered.…”

Section: Fig 7 Effects Of Puromycin Aminonucleoside On Bip Expressimentioning

confidence: 99%

“…C5b-9-induced sublethal cell injury may lead to a decline in cellular ATP, mitochondrial lipid perturbation, or loss of mitochondrial membrane potential (47)(48)(49), whereas at high doses, C5b-9 can induce mitochondrial damage and cell necrosis (50). Based on biochemical and morphologic observations (36,49), it is likely that, during complement-dependent GEC injury, integral membrane and secretory proteins are altered. Such proteins may include integrins, transporters, and/or cell junctional proteins, and these alterations may contribute to the permselectivity defect of the glomerular capillary wall in PHN.…”

Section: Fig 7 Effects Of Puromycin Aminonucleoside On Bip Expressimentioning

confidence: 99%

Complement C5b-9 Membrane Attack Complex Increases Expression of Endoplasmic Reticulum Stress Proteins in Glomerular Epithelial Cells

Cybulsky¹,

Takano²,

Papillon³

et al. 2002

Journal of Biological Chemistry

110

148

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In the passive Heymann nephritis (PHN) model of membranous nephropathy, complement C5b-9 induces glomerular epithelial cell (GEC) injury, proteinuria, and activation of cytosolic phospholipase A 2 (cPLA 2 ). This study addresses the role of endoplasmic reticulum (ER) stress proteins (bip, grp94) in GEC injury. GEC that overexpress cPLA 2 (produced by transfection) and "neo" GEC (which expresses cPLA 2 at a lower level) were incubated with complement (40 min), and leakage of constitutively expressed bip and grp94 from ER into cytosol was measured to monitor ER injury. Greater leakage of bip and grp94 occurred in complement-treated GEC that overexpress cPLA 2 , as compared with neo, implying that cPLA 2 activation perturbed ER membrane integrity. After chronic incubation (4 -24 h), C5b-9 increased bip and grp94 mRNAs and proteins, and the increases were dependent on cPLA 2 . Expression of bip-antisense mRNA reduced stimulated bip protein expression and enhanced complement-dependent GEC injury. Glomerular bip and grp94 proteins were up-regulated in proteinuric rats with PHN, as compared with normal control. Pretreatment of rats with tunicamycin or adriamycin, which increase ER stress protein expression, reduced proteinuria in PHN. Thus, C5b-9 injures the ER and enhances ER stress protein expression, in part, via activation of cPLA 2 . ER stress protein induction is a novel mechanism of protection from complement attack.

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“…Nucleated cells require multiple C5b-9 lesions for lysis, but at lower doses, C5b-9 induces sublethal (sublytic) injury and various metabolic effects (7). A previous study reported complement-dependent disruption of the actin microfilaments in cultured GEC (8), which may explain the altered cell-matrix interaction and impaired permselectivity that occur in podocytes in membranous nephropathy (8).…”

mentioning

confidence: 99%

Role of Guanine Nucleotide Exchange Factor-H1 in Complement-mediated RhoA Activation in Glomerular Epithelial Cells

Mouawad

Aoudjit

Jiang

et al. 2014

Journal of Biological Chemistry

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Background: Disruption of the actin cytoskeleton-dependent structural integrity of glomerular epithelial cells (GEC) leads to glomerular dysfunction. Results: We have identified molecular mechanisms through which the injury-causing complement complex induces cytoskeletal changes in GEC. Conclusion: Complement-induced activation of the ERK/GEF-H1/RhoA pathway protects GEC from cell death. Significance: This study furthers our understanding of mechanisms underlying GEC foot process effacement and functional impairment in immune mediated glomerular diseases.

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Complement-mediated injury reversibly disrupts glomerular epithelial cell actin microfilaments and focal adhesions

Cited by 78 publications

References 23 publications

Experimental membranous nephropathy redux

Experimental membranous nephropathy redux

Complement C5b-9 Membrane Attack Complex Increases Expression of Endoplasmic Reticulum Stress Proteins in Glomerular Epithelial Cells

Role of Guanine Nucleotide Exchange Factor-H1 in Complement-mediated RhoA Activation in Glomerular Epithelial Cells

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