Daniel Christoph, Schaub Kathrin, Amann Kerstin, Lawler Jack, Hugo Christian
Department of Nephrology and Hypertension, University Erlangen-Nürnberg, Loschgestr. 8, 91054 Erlangen, Germany.
Diabetes. 2007 Dec;56(12):2982-9. doi: 10.2337/db07-0551. Epub 2007 Sep 18.
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.
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.
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.
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.
转化生长因子-β（TGF-β）是导致糖尿病肾病发生的核心细胞因子，通常以无活性的前细胞因子复合物形式分泌，在与受体结合前必须被激活。我们团队最近的研究表明，血小板反应蛋白-1（TSP-1）是大鼠实验性肾小球肾炎中潜伏TGF-β的主要激活剂，但其在糖尿病肾病体内的作用尚不清楚。
通过链脲佐菌素注射诱导野生型小鼠（n = 27）和TSP-1缺陷型小鼠（n = 36）患1型糖尿病，并在7、9.5和20周后研究糖尿病肾病情况。通过免疫组织学评估肾脏组织学、TGF-β激活、基质积聚和炎症。使用实时PCR评估纤连蛋白和TGF-β的表达。此外，还检查了功能参数。
与野生型小鼠相比，TSP-1缺陷型小鼠肾小球内活性TGF-β的量显著降低，这通过用针对活性TGF-β、TGF-β信号分子磷酸化smad2/3或典型TGF-β靶基因产物纤溶酶原激活物抑制剂-1的特异性抗体染色来表明。相比之下，肾小球总TGF-β的量保持不变。TSP-1缺陷型小鼠的糖尿病肾病发展得到缓解，表现为肾小球硬化、肾小球基质积聚、足细胞损伤、炎症细胞肾浸润和肾功能参数显著降低。
我们得出结论，TSP-1是糖尿病肾病体内TGF-β的重要激活剂。TSP-1阻断疗法可能被认为是未来治疗糖尿病肾病的一种有前景的选择。
