title: Thrombospondin-1 plays a profibrotic and pro-inflammatory role during ureteric obstruction.
abstract: Thrombospondin-1 (TSP-1) is an endogenous activator of transforming growth factor-β (TGF-β), and an anti-angiogenic factor, which may prevent kidney repair. Here we investigated whether TSP-1 is involved in the development of chronic kidney disease using rats with unilateral ureteral obstruction, a well-known model to study renal fibrosis. Obstruction of 10 days duration induced inflammation, tubular cell atrophy, dilation, apoptosis, and proliferation, leading to interstitial fibrosis. TSP-1 expression was increased in parallel to that of collagen III and TGF-β. Relief of the obstruction at day 10 produced a gradual improvement in renal structure and function, the reappearance of peritubular capillaries, and restoration of renal VEGF content over a 7- to 15-day post-relief period. TSP-1 expression decreased in parallel with that of TGF-β1 and collagen III. Mice in which the TSP-1 gene was knocked out displayed less inflammation and had better preservation of renal tissue and the peritubular capillary network compared to wild-type mice. Additional studies showed that the inflammatory effect of TSP-1 was mediated, at least in part, by monocyte chemoattractant protein-1 and activation of the Th17 pathway. Thus, TSP-1 is an important profibrotic and inflammatory mediator of renal disease. Blockade of its action may be a treatment against the development of chronic kidney disease.
authors.affiliation: INSERM UNIT 702, Paris, France.
authors.forename: Naïke
authors.initials: N
authors.lastname: Bige
authors.forename: Nasim
authors.initials: N
authors.lastname: Shweke
authors.forename: Safa
authors.initials: S
authors.lastname: Benhassine
authors.forename: Chantal
authors.initials: C
authors.lastname: Jouanneau
authors.forename: Sophie
authors.initials: S
authors.lastname: Vandermeersch
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Dussaule
authors.forename: Christos
authors.initials: C
authors.lastname: Chatziantoniou
authors.forename: Pierre
authors.initials: P
authors.lastname: Ronco
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Boffa
mesh_terms: D000818:Animals; D017209:Apoptosis; D001284:Atrophy; D002196:Capillaries / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000378:metabolism; D002908:Chronic Disease; D024061:Collagen Type III / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D005786:Gene Expression Regulation; D018836:Inflammation Mediators / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009392:Nephrectomy; D009393:Nephritis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014517:Ureteral Obstruction / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D024061:Collagen Type III; D018836:Inflammation Mediators; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D019700:Thrombospondin 1; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse