Dissociation of mesangial cell migration and proliferation in experimental glomerulonephritis

Haseley, Leah A.; Hugo, Christian; Reidy, Michael A.; Johnson, Richard J.

doi:10.1046/j.1523-1755.1999.00641.x

Cited by 33 publications

(34 citation statements)

References 45 publications

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“…ings were confirmed by MTT assay where there were no changes in cell number or viability following incubation with either the antibodies or the metalloproteinase inhibitor. These results confirm a separate series of studies suggesting that factors affecting proliferation in MC are separate from those that effect migration (26,27).…”

Section: Discussionsupporting

confidence: 87%

The Role of ADAM 15 in Glomerular Mesangial Cell Migration

Martin

Eynstone

Davies

et al. 2002

Journal of Biological Chemistry

106

101

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Mesangial cells (MC) occupy the core of the renal glomerulus and are surrounded by a mesangial matrix. In certain diseases, MC migrate through this matrix into the pericapillary space. The mechanisms involved, however, are poorly understood. Members of the ADAM (A Disintegrin And Metalloproteinase) family of membrane proteins have the potential to be key modulators of cellmatrix interactions through the activities of their constituent domains. We have studied the possible role of ADAM 15 in human (H) MC migration in vitro. HMC ADAM 15 was expressed at low levels in serum-free medium but was increased during migration. Antibodies to the individual domains of ADAM 15 and the incorporation of antisense ADAM 15, (but not control oligonucleotide) inhibited this migration. Furthermore, inhibition of migration by the broad spectrum metalloproteinase inhibitor BB3103, demonstrated that metalloproteinase activity was essential for migration. ADAM 15, extracted from HMC membranes, was an active metalloproteinase, which degraded both type IV collagen and gelatin prepared from fibrillar collagen. Activity was inhibited by EDTA but not by phenylmethylsulfonyl fluoride. This is the first report of the potential of ADAM 15 for involvement in the restructuring of the mesangial matrix and in the migration of MC in disease.Mesangial cell migration through the mesangial matrix and into the pericapillary space is a feature of a number of renal diseases, including mesangiocapillary glomerulonephritis (1). In addition, it appears that extracellular matrix components such as fibronectin (2), thrombospondin (3), and heparin-like glycosaminoglycans (4) can modulate this migration. This movement of cells must involve disengagement from and remodeling of the surrounding extracellular matrix. Possible mediators for this remodeling include a variety of serine proteinases and matrix metalloproteinases (MMPs) 1 but also the newly described ADAM family of molecules.The ADAMs are a family of cell surface molecules that possess both disintegrin and MMP domains. The disintegrin domain of these molecules resembles the sequence of the snake venom disintegrins and binds to integrins on the cell surface (5). This displaces the integrin from its matrix target, thus freeing the cell from its substrate. Moreover the binding of a disintegrin to integrins on its own cell membrane in addition to those on adjacent cells is a possibility, freeing both cells from their substratum. Furthermore, because the ADAM molecules are proteolytically processed (6), cleavage of the ADAM may also take place, releasing the bound disintegrin from the cell and freeing the cell from the matrix. In addition, the binding of the disintegrin domain to integrins on adjacent cells may direct the MMP to the site of integrin/matrix interaction resulting in matrix degradation and facilitating cell migration.The deduced structure of the MMP catalytic domain appears functional in many of the 30 or more ADAM family members (that is, there is an active site consensus sequence) (7), wher...

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Section: Discussionsupporting

confidence: 87%

The Role of ADAM 15 in Glomerular Mesangial Cell Migration

Martin

Eynstone

Davies

et al. 2002

Journal of Biological Chemistry

106

101

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“…A higher FGF2 level can induce podocytopathy through the induction of caspase-3 1 and can simultaneously stimulate cell proliferation and matrix increase in mesangial cells. 6,26 In general, Rho regulates the formation of stress fibers, whereas Cdc42 and Rac1 regulate that of filopodia and lamellipodia, respectively. In previous reports, increased active Rac1 signaling in podocytes produced albuminuria.…”

Section: Glypican-5 In Diabetic Nephropathymentioning

confidence: 99%

Glypican-5 Increases Susceptibility to Nephrotic Damage in Diabetic Kidney

Okamoto

Honda

Doi

et al. 2015

The American Journal of Pathology

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Type 2 diabetes mellitus is a leading health issue worldwide. Among cases of diabetes mellitus nephropathy (DN), the major complication of type 2 diabetes mellitus, the nephrotic phenotype is often intractable to clinical intervention and demonstrates the rapid decline of renal function to end-stage renal disease. We recently identified the gene for glypican-5 (GPC5), a cell-surface heparan sulfate proteoglycan, as conferring susceptibility for acquired nephrotic syndrome and additionally identified an association through a genomewide association study between a variant in GPC5 and DN of type 2 diabetes mellitus. In vivo and in vitro data showed a progressive increase of GPC5 in type 2 DN along with severity; the excess was derived from glomerular mesangial cells. In this study, diabetic kidney showed that accumulation of fibroblast growth factor (Fgf)2 strikingly induced progressive proteinuria that was avoided in Gpc5 knockdown mice. The efficacy of Gpc5 inhibition was exerted through expression of the Fgf receptors 3 and 4 provoked in the diabetic kidney attributively. Extraglomerular Fgf2 was pathogenic in DN, and the deterrence of Gpc5 effectively inhibited the glomerular accumulation of Fgf2, the subsequent increase of mesangial extracellular matrix, and the podocytes' small GTPase activity. These findings elucidate the pivotal role of GPC5, identified as a susceptible gene in the genome-wide association study, in hyperglycemia-induced glomerulopathy. Among diabetes mellitus nephropathy (DN) cases, intractable dysfunction rapidly propagating to end-stage renal disease often accompanies the nephrotic proteinuria phenotype. Our recent study implicated glypican-5 (GPC5) as a susceptible gene for acquired nephrotic syndrome and demonstrated its functional significance by using podocyte-specific knockout mice; a genome-wide association study of DN satisfying the criterion of nephrotic syndrome also clarified GPC5 as the candidate gene [odds ratio 1.45 (95% CI, 1.18e1.79)].

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“…5,7 Blocking of FGF-2 in the anti-Thy1 model resulted in inhibition of mesangial cell proliferation without significant effects on cell migration. 7 In the Habu snake venom glomerulonephritis model, MC migrated during the first 24 h after disease induction without significant proliferation. 5 Therefore, inhibition of cell proliferation is not linked with simultaneous inhibition of migration in a general fashion.…”

Section: Discussionmentioning

confidence: 99%

“…5 Therefore, inhibition of cell proliferation is not linked with simultaneous inhibition of migration in a general fashion. 7 Nevertheless, many growth factors have the potential to act as both mitogens and chemoattractants. 23 The apparent link of cellular proliferation and migration during glomerular repopulation in the anti-Thy1 model suggests that cell cycle regulation and cell migration may be regulated by similar pathways.…”

Section: Discussionmentioning

confidence: 99%

“…The exact protocol for our in vivo migration assay has been previously described in detail. 3,4,7 Experimental mesangial proliferative glomerulonephritis (anti-Thy1 model) was induced by a single injection of the monoclonal anti-Thy1.1 antibody OX-7 (0.35 ml/100 g bw) in male Sprague-Dawley rats 13 (Charles River, Sulzfeld, Germany). 54, 62, and 70 h after disease induction, intraperitoneal injections of 10 mg/100 g bw BrdU were given in all rats to label surviving mesangial reserve cells located at the extraglomerular mesangium and hilar region that just start to repopulate the glomerulus via proliferation (DNA synthesizing) and migration.…”

Section: Animal Model and Experimental Designmentioning

confidence: 99%

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The Rapamycin derivative RAD inhibits mesangial cell migration through the CDK-inhibitor p27KIP1

Daniel

Pippin

Shankland

et al. 2004

Laboratory Investigation

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The link between mesangial cell (MC) proliferation and migration during glomerular repair in the experimental mesangial proliferative glomerulonephritis suggests that cell cycle regulation and cell migration require similar pathways, such as cell cycle proteins. The immunosuppressant RAD inhibits mesangial cell (MC) proliferation via G1/S arrest. Moreover, RAD dramatically impairs glomerular healing in the anti-Thy1 model. We tested the hypothesis that RAD alters MC migration in vitro and that this effect was mediated by the CDK-inhibitors p21 CIP1 and p27 KIP1 . Using a modified Boyden chamber in vitro migration assay, our results showed that RAD dose dependently (1-50 nM) inhibited fibronectin-induced chemotaxis in wild-type (wt) MC. RAD treatment prevented the decrease in p27 KIP1 induced by mitogenic growth factors, but had no effect on p21 CIP1 by Western blot analysis. The antimigratory effect of RAD in wt MC was substantially dependent on p27 KIP1 , but not p21 CIP1 , since the inhibitory effects of 1-10 nM RAD on MC migration were similar in p21 CIP1 deficient and wild-type MC. The effect of RAD on MC migration was also examined in the anti-Thy1 model by BrdU-labeling of proliferating MC on day 3 that typically repopulate the glomerulus from the hilus. A control biopsy on day 3 was taken to define the starting point prior to the initiation of RAD (3 mg/kg or placebo). MC migration was determined on day 7 by measuring the distances of BrdU-labeled MC (OX-7 þ /BrdU þ cells) from the glomerular hilus using computerized morphometry. RAD significantly reduced the migratory response of BrdU-labeled MC compared to controls. We conclude that the immunosuppressant RAD effectively inhibits MC migration in vivo and in vitro thereby limiting the normal glomerular repair process after severe injury. Moreover, RAD-induced inhibition of MC migration in vitro is partially mediated by the CDK-inhibitor p27 KIP1 , but not p21 CIP1 .

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Dissociation of mesangial cell migration and proliferation in experimental glomerulonephritis

Abstract: These studies demonstrate that bFGF is an important mediator of MC proliferation but that it does not significantly influence MC migration. This is the first demonstration showing that the mediators effecting proliferation can be dissociated from those mediating migration in renal injury.

Cited by 33 publications

References 45 publications

The Role of ADAM 15 in Glomerular Mesangial Cell Migration

The Role of ADAM 15 in Glomerular Mesangial Cell Migration

Glypican-5 Increases Susceptibility to Nephrotic Damage in Diabetic Kidney

The Rapamycin derivative RAD inhibits mesangial cell migration through the CDK-inhibitor p27KIP1

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