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  • Title: Thrombospondin-1 is an endogenous activator of TGF-beta in experimental diabetic nephropathy in vivo.
    Author: Daniel C, Schaub K, Amann K, Lawler J, Hugo C.
    Journal: Diabetes; 2007 Dec; 56(12):2982-9. PubMed ID: 17878288.
    Abstract:
    OBJECTIVE: Transforming growth factor-beta (TGF-beta), the central cytokine responsible for the development of diabetic nephropathy, is usually secreted as a latent procytokine complex that has to be activated before it can bind to its receptors. Recent studies by our group demonstrated that thrombospondin-1 (TSP-1) is the major activator of latent TGF-beta in experimental glomerulonephritis in the rat, but its role in diabetic nephropathy in vivo is unknown. RESEARCH DESIGN AND METHODS: Type 1 diabetes was induced in wild-type (n = 27) and TSP-1-deficient mice (n = 36) via streptozotocin injection, and diabetic nephropathy was investigated after 7, 9.5, and 20 weeks. Renal histology, TGF-beta activation, matrix accumulation, and inflammation were assessed by immunohistology. Expression of fibronectin and TGF-beta was evaluated using real-time PCR. Furthermore, functional parameters were examined. RESULTS: In TSP-1-deficient compared with wild-type mice, the amount of active TGF-beta within glomeruli was significantly lower, as indicated by staining with specific antibodies against active TGF-beta or the TGF-beta signaling molecule phospho-smad2/3 or the typical TGF-beta target gene product plasminogen activator inhibitor-1. In contrast, the amount of glomerular total TGF-beta remained unchanged. The development of diabetic nephropathy was attenuated in TSP-1-deficient mice as demonstrated by a significant reduction of glomerulosclerosis, glomerular matrix accumulation, podocyte injury, renal infiltration with inflammatory cells, and renal functional parameters. CONCLUSIONS: We conclude that TSP-1 is an important activator of TGF-beta in diabetic nephropathy in vivo. TSP-1-blocking therapies may be considered a promising future treatment option for diabetic nephropathy.
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