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: Naïke Bige, Nasim Shweke, Safa Benhassine, Chantal Jouanneau, Sophie Vandermeersch, Jean-Claude Dussaule, Christos Chatziantoniou, Pierre Ronco, Jean-Jacques Boffa
• Journal: Kidney international (Kidney Int) Vol. 81 Issue 12 Pg. 1226-38 (Jun 2012) ISSN: 1523-1755 [Electronic] United States
• PMID: 22418977 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ccl2 protein, mouse
• Chemokine CCL2
• Collagen Type III
• Inflammation Mediators
• Tgfb1 protein, mouse
• Tgfb1 protein, rat
• Thrombospondin 1
• Transforming Growth Factor beta1
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse

Topics

• Animals
• Apoptosis
• Atrophy
• Capillaries (metabolism, pathology)
• Cell Proliferation
• Chemokine CCL2 (metabolism)
• Chronic Disease
• Collagen Type III (metabolism)
• Disease Models, Animal
• Fibrosis
• Gene Expression Regulation
• Inflammation Mediators (metabolism)
• Kidney (blood supply, metabolism, pathology)
• Kidney Diseases (etiology, genetics, metabolism, pathology)
• Male
• Mice
• Mice, Knockout
• Nephrectomy
• Nephritis (etiology, genetics, metabolism, pathology, prevention & control)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction
• Thrombospondin 1 (deficiency, genetics, metabolism)
• Time Factors
• Transforming Growth Factor beta1 (metabolism)
• Ureteral Obstruction (complications, genetics, metabolism, pathology)
• Vascular Endothelial Growth Factor A (metabolism)