Hyperglycemia and Diabetic Kidney Disease: The Case for Transforming Growth Factor–β as a Key Mediator
Hyperglycemia and Diabetic Kidney Disease: The Case for Transforming Growth Factor–β as a Key Mediator
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DOI：
10.2337/diab.44.10.1139
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发表时间：
1995-10
期刊：
影响因子：
7.7
通讯作者：
K. Sharma;F. Ziyadeh
中科院分区：
文献类型：
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作者：
K. Sharma;F. Ziyadeh
肾细胞是转化生长因子（TGF）-β的丰富来源，并且它们作为其作用的靶点。我们的假设是，肾脏中TGF-β系统的激活与糖尿病肾病的发展有关，这是因为TGF-β和高环境葡萄糖对肾细胞生长和细胞外基质代谢的作用非常相似。在高葡萄糖浓度下培养的近端小管细胞和肾小球系膜细胞表达增加的TGF-β1 mRNA和蛋白水平，并且用抗TGF-β抗体处理导致预防高糖诱导细胞肥大和刺激胶原蛋白生物合成的作用。由不同研究小组进行的几项体内研究已经报道了TGF-β在人类和实验性糖尿病的肾小球中的过表达。我们还观察到，胰岛素依赖性糖尿病BB大鼠和NOD小鼠中肾肥大的发展与肾脏中TGF-β1表达的增加有关，并且在糖尿病链脲佐菌素小鼠模型中短期施用能够中和TGF-β活性的抗体导致整个肾脏和肾小球肥大的减弱以及编码基质组分的mRNA的过表达。总之，这些发现与以下假设一致：糖尿病状态刺激肾脏中的TGF-β表达，反过来，这种生长因子可能以自分泌/旁分泌方式介导糖尿病肾病的一些主要早期表现。要证明肾小球TGF-β的上调与随后糖尿病肾小球硬化的发展之间存在因果关系，需要进行长期干预性研究，以阻断肾脏中的TGF-β系统。
Renal cells are a rich source of transforming growth factor (TGF)-β, and they serve as targets for its actions. Our hypothesis that activation of the TGF-β system in the kidney is implicated in the development of diabetic renal disease stems from the close similarity of actions of TGF-β and high ambient glucose on renal cell growth and extracellular matrix metabolism. Proximal tubule cells and glomerular mesangial cells cultured in high glucose concentration express increased TGF-β1 mRNA and protein levels, and treatment with anti-TGF-β antibodies results in prevention of the effects of high glucose to induce cellular hypertrophy and stimulate collagen biosynthesis. Several in vivo studies by different groups of investigators have reported overexpression of TGF-β in the glomeruli in human and experimental diabetes. We have also observed that the development of renal hypertrophy in the insulin-dependent diabetic BB rat and NOD mouse is associated with increased expression of TGF-β1 in the kidney and that short-term administration of antibodies capable of neutralizing the activity of TGF-β in the streptozotocin mouse model of diabetes results in attenuation of whole kidney and glomerular hypertrophy and overexpression of mRNAs encoding matrix components. Together, these findings are consistent with the hypothesis that the diabetic state stimulates TGF-β expression in the kidney and that in turn this growth factor may mediate, in an autocrine/paracrine manner, some of the principal early manifestations of diabetic renal disease. Demonstrating a causal link between upregulation of glomerular TGF-β and the subsequent development of diabetic glomerulosclerosis will require long-term interventional studies designed to intercept the TGF-β system in the kidney.