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Thrombospondin-1 is an endogenous activator of TGF-beta in experimental diabetic nephropathy in vivo

From the *Department of Nephrology and Hypertension,
**Department of Pathology, University Erlangen-Nürnberg, Erlangen, Germany
#Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, USA

Objective: TGF-ß, 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-ß in experimental glomerulonephritis in the rat, but its role in diabetic nephropathy in vivo is unknown.

Research design and methods: Type I 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-ß activation, matrix accumulation and inflammation were assessed by immunohistology. Expression of fibronectin and TGF-ß was evaluated using Real-time PCR. Furthermore, functional parameters were examined.

Results: In TSP-1 deficient compared to wt mice, the amount of active TGF-ß within glomeruli was significantly lower as indicated by staining with specific antibodies either against active TGF-ß or the TGF-ß signaling molecule phospho-smad2/3 or the typical TGF-ß target gene product plasminogen activator inhibitor-1. In contrast, the amount of glomerular total TGF-ß 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 as well as renal functional parameters.

Conclusion: We conclude that TSP-1 is an important activator of TGF-ß in diabetic nephropathy in vivo. TSP-1 blocking therapies may be considered a promising future treatment option for diabetic nephropathy.

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