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


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.
Daniel
Christoph
C
Department of Nephrology and Hypertension, University Erlangen-Nürnberg, Loschgestr. 8, 91054 Erlangen, Germany. christoph.a.daniel@rzmail.uni-erlangen.de
Schaub
Kathrin
K
Amann
Kerstin
K
Lawler
Jack
J
Hugo
Christian
C
D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D007668:Kidney / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019700:Thrombospondin 1 / Q000172:deficiency / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000502:physiology*
D001786:Blood Glucose; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta