P2 receptor antagonist PPADS inhibits mesangial cell proliferation in experimental mesangial proliferative glomerulonephritis

Rost, Sylvia; Daniel, Christoph; Schulze-Lohoff, Eckhard; Bäumert, Hans G.; Lambrecht, Günter; Hugo, Christian

doi:10.1046/j.1523-1755.2002.00621.x

Cited by 31 publications

(45 citation statements)

References 33 publications

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“…In experimental mesangial proliferative glomerulonephritis in the rat (anti-Thy-1 model), there is a pronounced mesangial cell proliferative response leading to glomerular hypercellularity. In the anti-Thy-1 model, PPADS specifically and dose-dependently reduced early (day 3) but not late (day 8) mesangial cell proliferation [313]. The authors also reported that P2Y 2 and P2Y 6 receptors showed a transient marked increase in expression during anti-Thy-1 disease.…”

Section: Nephritismentioning

confidence: 88%

Purinergic signalling in the kidney in health and disease

Burnstock

Evans

Bailey

2013

Purinergic Signalling

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The involvement of purinergic signalling in kidney physiology and pathophysiology is rapidly gaining recognition and this is a comprehensive review of early and recent publications in the field. Purinergic signalling involvement is described in several important intrarenal regulatory mechanisms, including tuboglomerular feedback, the autoregulatory response of the glomerular and extraglomerular microcirculation and the control of renin release. Furthermore, purinergic signalling influences water and electrolyte transport in all segments of the renal tubule. Reports about purine-and pyrimidine-mediated actions in diseases of the kidney, including polycystic kidney disease, nephritis, diabetes, hypertension and nephrotoxicant injury are covered and possible purinergic therapeutic strategies discussed.

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Section: Nephritismentioning

confidence: 88%

Purinergic signalling in the kidney in health and disease

Burnstock

Evans

Bailey

2013

Purinergic Signalling

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“…Isolation of glomeruli and northern-blot analysis using 20 mg total RNA per lane were done as previously described. 13 The blots were hybridized with an 1.0-kb rat transgelin (SM actin 22-alpha) cDNA fragment kindly provided by Dr C Shanahan (Cambridge, UK). 15 …”

Section: Northern-blot Analysis Of Transgelin Expressionmentioning

confidence: 99%

“…13 Total RNA was extracted using the RNeasy RNA isolation system (Qiagen, Hilden, Germany) according to manufacturer's instructions and quantified by spectrophotometry (Ultrospec 3000 pro, Amersham Biosciences, Freiburg, Germany). All RNA samples showed A260/280 ratios between 1.9 and 2.1.…”

Section: Preparation Of Glomerular Total Rna and Gene Expression Analmentioning

confidence: 99%

Transgelin is a marker of repopulating mesangial cells after injury and promotes their proliferation and migration

Daniel

Lüdke

Wagner

et al. 2012

Laboratory Investigation

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Mesangial cell (MC) migration is essential during glomerular repair and kidney development. The aim of the study was to identify marker/player for glomerular progenitor/reserve cells migrating into the glomerulus after MC injury and during glomerulogenesis in the rat. Experimental mesangial proliferative nephritis was induced in Sprague Dawley rats by intravenous injection of OX-7 antibody. We investigated mRNA expression profiles in isolated glomeruli from on days 0, 1, 2, 3, and 5 after induction of anti-Thy1 nephritis using Affymetrix microarray technology. Using self-organizing maps, transgelin was identified as a new marker for repopulating glomerular cells. Expression of transgelin during anti-Thy1 nephritis was investigated by northern blot, real-time PCR, western blot, and immunohistochemistry. Migration and proliferation assays using isolated MCs after transgelin knockdown by siRNA were performed to investigate the potential role of transgelin during glomerular repopulation. Transgelin mRNA was not detected in healthy glomeruli. It was strongly upregulated during the repopulation process starting on day 1, continued to be increased until day 5 and disappeared on day 7. Transgelin was specifically expressed at the edge of the migratory front during glomerular repopulation as indicated by transgelin/OX-7 double staining. Transgelin expression was similar in migrating vs non-migrating MCs in vitro. Blocking of transgelin expression by siRNA treatment resulted in inhibition of MC migration and proliferation. Transgelin was also expressed in MCs during glomerulogenesis and in biopsies from patients with IgA nephritis. In conclusion, transgelin in the kidney is upregulated in repopulating MCs in vivo and supports their migratory and proliferative repair response after injury.

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“…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%

“…4,13 MC were identified using an antibody against OX-7 (Serotec, Ltd., Kidlington, Oxford, UK). 4 The following additional antibodies were used in this study: Peroxidase-labeled Fab-fragments against BrdU (Boehringer, Mannheim, Germany); polyclonal rabbit anti-p21 CIP1 and anti-p27 KIP1 antibodies (Santa Cruz Biotechnology, Heidelberg, Germany); 8 mouse monoclonal antibody against the total p70 S6 kinase as well as the phosphorylated p-p70 S6 kinase (Santa Cruz).…”

Section: Immunohistochemistrymentioning

confidence: 99%

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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P2 receptor antagonist PPADS inhibits mesangial cell proliferation in experimental mesangial proliferative glomerulonephritis

Abstract: These data strongly suggest an in vivo role for extracellular nucleotides in mediating early MC proliferation after MC injury.

Cited by 31 publications

References 33 publications

Purinergic signalling in the kidney in health and disease

Purinergic signalling in the kidney in health and disease

Transgelin is a marker of repopulating mesangial cells after injury and promotes their proliferation and migration

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

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