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Thrombospondin-1 Is an Endogenous Activator of TGF-ß in Experimental Diabetic Nephropathy In Vivo

¹ Department of Nephrology and Hypertension, University Erlangen-Nürnberg, Erlangen, Germany
² Department of Pathology, University Erlangen-Nürnberg, Erlangen, Germany
³ Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts

Address correspondence and reprint requests to Christoph Daniel, PhD, University Erlangen-Nürnberg, Loschgestr. 8, 91054 Erlangen, Germany. E-mail: christoph.a.daniel{at}rzmail.uni-erlangen.de

Abbreviations: LAP, latency-associated protein; mAb, monoclonal antibody; PAI-1, plasminogen activator inhibitor 1; PAS, periodic acid Schiff; PCNA, proliferating cell nuclear antigen; STZ, streptozotocin; TGF-ß, transforming growth factor-ß’3b; TSP-1, thrombospondin-1; TUNEL, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling

OBJECTIVE—Transforming growth factor-ß (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 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-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 with wild-type mice, the amount of active TGF-ß within glomeruli was significantly lower, as indicated by staining with specific antibodies 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, and renal functional parameters.

CONCLUSIONS—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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