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.

Urinary excretion of angiogenesis regulatory factors and renal injury markers in chronic glomerulonephritis: Significance in the assessment of progression

“…по многим функциям противоположен VEGF [7,8,17]. Взаимодействуя с трансформирующим β-фактором роста (TGF-β), THBS1 регулирует клеточно-матриксные взаимодействия и оказывает профиброгенное действие [18,19].…”

Matricellular Proteins and Organ Fibrosis

“…The authors treated primary isolated mesangial cells with leptin and showed that leptin-stimulated ECM production was abolished by TSP1 deficiency (21). Moreover, TSP1 deficiency or treatment with shRNA against TSP1 was protective in mouse UUO, leading to decreased inflammation and fibrosis, increased VEGF expression and preserved endothelial capillary network (22,23). TSP1 was also found to mediate high-fat diet-induced skeletal muscle fibrosis or diabetes-induced myocardial fibrosis by either inducing collagen expression or inhibiting collagen degradation through regulation of MMP2 and MMP9 activities, respectively (24,25).…”

Rôle de la thrombospondine-1 dans le développement des maladies rénales

“…En conditions pathologiques, elle a été analysée in vivo dans différents modèles de néphropathies. Après ischémie-reperfusion [27], réduction néphronique [28], obstruction urétérale unilatérale [29], mais aussi au cours du vieillissement rénal [30], du diabète [31] et de nombreuses autres néphropathies glomérulaires expérimentales [32,33], les cellules épithéliales tubulaires expriment de novo la TSP-1. In vitro, l'hypoxie [34] et l'enrichissement du milieu de culture en glucose [31,35] [33].…”

“…Chez le rat, l'obstruction urétérale unilatérale induit une expression de novo de l'ARNm de tsp-1 et de la protéine TSP-1 par les tubules lésés. Cette expression est corrélée au contenu rénal en TGF-, et diminue parallèlement à celle du TGF- après désobstruction urétérale [29]. L'inhibition spécifique de l'activation du TGF- par la TSP-1 (via l'administration du peptide LSKL) a été étudiée dans trois modèles de néphropathie.…”

“…Après induction d'un diabète par la streptozocine chez les souris TSP-1 KO, l'expression glomérulaire de TGF-, des Smad2 et -3 phosphorylées et de PAI-1 (plasminogen activator inhibitor-1), l'accumulation mésangiale de fibronectine et de collagène IV, les lésions podocytaires, l'infiltration interstitielle par les macrophages et les lymphocytes, et la protéinurie sont réduites [44]. Enfin, l'activation rénale du TGF- et les lésions tubulo-interstitielles induites par l'obstruction urété-rale unilatérale sont atténuées chez la souris TSP-1 KO [29]. Notre équipe a également observé cette protection tubulaire chez les souris TSP1-KO après obstruction urétérale unilatérale.…”