Pugliese G, Pricci F, Pesce C, Romeo G, Lenti E, Caltabiano V, Vetri M, Purrello F, Di Mario U
Department of Experimental Medicine and Pathology, La Sapienza University of Rome, Italy.
Diabetes. 1997 Jul;46(7):1198-206. doi: 10.2337/diab.46.7.1198.
In this study, we investigated 1) whether long-term restoration of euglycemia by means of pancreatic islet transplants is capable of preventing and/or reversing renal functional and structural alterations in an experimental model of insulin-deficient diabetes, and 2) whether changes in extracellular matrix (ECM) and cell turnover at the glomerular level and biochemical abnormalities associated with hyperglycemia correlate with the renal outcome after transplantation. Male Lewis rats, rendered diabetic by intravenous injection of streptozotocin, underwent homologous islet transplantation via the portal vein at 2 weeks (study A), at 4 months (study B), and at 8 months (study C) after the induction of diabetes and killed 12 months after transplantation in study A and 4 months after transplantation in studies B and C. Age-matched nondiabetic and untreated diabetic rats were used as control animals and were studied at 4, 8, and 12 months. In the untreated diabetic animals, metabolic derangement was associated with increased erythrocyte polyol and fructose levels, tail-tendon content of advanced glycation end products (AGEs), total proteinuria, albuminuria, kidney weight, and mean glomerular volume as well as with marked glomerular and extraglomerular lesions. Glomerular gene expression for the ECM components fibronectin and collagen IV and for TGF-beta was also increased, whereas glomerular cell proliferation was unaffected by diabetes. In study A, changes in renal function and structure observed in diabetic rats at 12 months were completely prevented by successful islet transplants. In study B, all functional and structural abnormalities detected in diabetic rats at 4 months of disease duration were virtually reversed by 4 months of euglycemia in transplanted animals, whereas they progressed further in untreated diabetic rats. In study C, the course of functional and structural changes observed in untreated diabetic rats was not reversed by islet transplantation. Likewise, tissue AGE accumulation and particularly upregulation of glomerular ECM and transforming growth factor (TGF)-beta gene expression, which are believed to play a role in the pathogenesis of altered renal function and structure in diabetes, were normalized in transplanted rats from study A and study B, but not in those from study C. These experiments show that restoration of euglycemia by islet transplants is capable of preventing experimental diabetic glomerulopathy and reversing early changes in renal function and structure induced by diabetes. In a later phase of the disease, when glomerular matrix gene expression becomes independent of hyperglycemia, possibly because of the persistent increase in tissue AGE accumulation, metabolic control is not capable of reversing renal abnormalities.
在本研究中，我们调查了：1）通过胰岛移植长期恢复正常血糖水平是否能够预防和/或逆转胰岛素缺乏型糖尿病实验模型中的肾功能和结构改变；2）肾小球水平的细胞外基质（ECM）和细胞更新变化以及与高血糖相关的生化异常是否与移植后的肾脏结局相关。通过静脉注射链脲佐菌素使雄性Lewis大鼠患糖尿病，在糖尿病诱导后2周（研究A）、4个月（研究B）和8个月（研究C）经门静脉进行同种异体胰岛移植，并在研究A移植后12个月、研究B和C移植后4个月处死大鼠。将年龄匹配的非糖尿病和未治疗的糖尿病大鼠作为对照动物，并在4、8和12个月时进行研究。在未治疗的糖尿病动物中，代谢紊乱与红细胞多元醇和果糖水平升高、晚期糖基化终产物（AGEs）的尾腱含量、总蛋白尿、白蛋白尿、肾脏重量和平均肾小球体积增加以及明显的肾小球和球外病变有关。肾小球中ECM成分纤连蛋白和IV型胶原以及TGF-β的基因表达也增加，而肾小球细胞增殖不受糖尿病影响。在研究A中，成功的胰岛移植完全预防了糖尿病大鼠在12个月时观察到的肾功能和结构变化。在研究B中，移植动物通过4个月的正常血糖水平几乎逆转了病程4个月的糖尿病大鼠中检测到的所有功能和结构异常，而未治疗的糖尿病大鼠中的异常则进一步进展。在研究C中，胰岛移植未逆转未治疗的糖尿病大鼠中观察到的功能和结构变化过程。同样，组织AGE积累，特别是肾小球ECM和转化生长因子（TGF）-β基因表达的上调，被认为在糖尿病肾功能和结构改变的发病机制中起作用，在研究A和研究B的移植大鼠中恢复正常，但在研究C的大鼠中未恢复正常。这些实验表明，通过胰岛移植恢复正常血糖水平能够预防实验性糖尿病肾小球病，并逆转糖尿病引起的肾功能和结构早期变化。在疾病的后期，当肾小球基质基因表达变得独立于高血糖时，可能是由于组织AGE积累持续增加，代谢控制无法逆转肾脏异常。
