Thrombospondin-1 plays a profibrotic and pro-inflammatory role during ureteric obstruction

• Published in: Kidney international Vol. 81; no. 12; pp. 1226 - 1238
• Main Authors: Bige, Naïke, Shweke, Nasim, Benhassine, Safa, Jouanneau, Chantal, Vandermeersch, Sophie, Dussaule, Jean-Claude, Chatziantoniou, Christos, Ronco, Pierre, Boffa, Jean-Jacques
• Format: Journal Article
• Language: English
• Published: Basingstoke Elsevier Inc 01.06.2012; Nature Publishing Group; Elsevier Limited
• Subjects: Animals; Apoptosis; Atrophy; Biochemistry, Molecular Biology; Biological and medical sciences; Capillaries; Capillaries - metabolism; Capillaries - pathology; Cell Proliferation; Chemokine CCL2; Chemokine CCL2 - metabolism; Chronic Disease; Collagen Type III; Collagen Type III - metabolism; Disease Models, Animal; Fibrosis; Gene Expression Regulation; Genomics; Inflammation Mediators; Inflammation Mediators - metabolism; Kidney; Kidney - blood supply; Kidney - metabolism; Kidney - pathology; Kidney Diseases; Kidney Diseases - etiology; Kidney Diseases - genetics; Kidney Diseases - metabolism; Kidney Diseases - pathology; Kidneys; Life Sciences; Male; Medical sciences; Mice; Mice, Knockout; Nephrectomy; Nephritis; Nephritis - etiology; Nephritis - genetics; Nephritis - metabolism; Nephritis - pathology; Nephritis - prevention & control; Nephrology. Urinary tract diseases; Rats; Rats, Sprague-Dawley; renal fibrosis; renal progression; Signal Transduction; TGF-β; Thrombospondin 1; Thrombospondin 1 - deficiency; Thrombospondin 1 - genetics; Thrombospondin 1 - metabolism; Time Factors; Transforming Growth Factor beta1; Transforming Growth Factor beta1 - metabolism; Ureteral Obstruction; Ureteral Obstruction - complications; Ureteral Obstruction - genetics; Ureteral Obstruction - metabolism; Ureteral Obstruction - pathology; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor A - metabolism; renal fibrosis; TGF-β; renal progression; Kidney disease; Nephrology; Urinary system disease; Prognosis; Transforming growth factor β; Renal fibrosis; Ureteral obstruction; Ureteral disease; Inflammation; Urinary tract disease; Thrombospondin 1; Kidney; Urology; Urinary system; Evolution; Antiangiogenic agent
• ISSN: 0085-2538; 1523-1755; 1523-1755
• DOI: 10.1038/ki.2012.21

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.