VASCULAR PERMEABILITY IN DIABETIC NEPHROPATHY

糖尿病肾病的血管通透性

• 批准号: 6342524
• 负责人: MICHAEL S GOLIGORSKY
• 金额: $ 21.35万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6342524
• 关键词: angiogenesis; angiogenesis factor; angiogenesis inhibitors; diabetic nephropathy; disease /disorder etiology; extracellular matrix proteins; hemodynamics; interstitial cystitis; laboratory rat; mixed tissue /cell culture; nitric oxide; pathologic process; renal ischemia /hypoxia; respiratory oxygenation; streptozotocin; toxicology; vascular endothelial growth factors; vascular endothelium permeability

The recent description of interstitial fibrosis and renal failure in a streptozotocin model of diabetes in rats subjected to a brief period of renal ischemia provides a good model of human DN and may shed light on the potential pathogenetic mechanisms of this phenomenon. Such new observations, unexplained by the currently prevailing hyperfiltration hypothesis, call for alterative hypoxia-inducible mechanisms of progression in DN. Indeed, it has been demonstrated that hypoxia is itself a potent regulator of gene expression, acting via transcriptional control and mRNA stability to alter the expression of a wide variety of hormones, growth factors, vasoactive compounds and molecules involved in intermediary metabolism. Prominent among hypoxia-inducible growth factors is vascular endothelial growth factor/vascular permeability factor (VEGF/VPF). We hypothesize that the combination of elevated VEGF production, increased post-glomerular vascular permeability and transduction of glycosylated proteins trigger the cascade of events which lead to interstitial fibrosis. Specifically, transudated glycated serum constituents, on the other hand, stimulate fibroblast proliferation, differentiation into myofibroblasts and synthesis of matrix proteins, while on the other hand, these glycosylated products inhibit angiogenesis, thus maintaining the state of chronic hypoxia. This hypothesis will be tested functionally (hemodynamic parameters, tissue oxygenation, expression of angiogenic and angiostatic factors, effects of anti-VEGF and VEGF on these parameters), morphologically (mapping of glycated proteins, proteoglycans, glycoproteins, and other markets of vascular permeability), using approaches of cell biology (isolation of renal fibroblasts, co- cultures of endothelial cells with fibroblasts, parameters characterizing cell cycle and their modification by glycated matrix/serum proteins utilized as a substratum, expression of genes and gene products participating in matrix synthesis and degradation and the influence of glycated proteins on these parameters,) cellular physiological approaches (endothelial cell migration and angiogenic potential under the conditions of dysfunctional NO synthase or perturbed repertoire of glycated matrix proteins, balance between the vascular permeability and angiogenesis as affected by glycated proteins and VEGF, and the potential resolution of fibrosis by angiogenic promoters). The proof of this unifying hypothesis of endothelium-dependent fibroblast activation feeding back to inhibit angiogenesis, will require studies on several levels of complexity-from molecular and cellular biology to whole animal physiology-and warrants the combined efforts of three problem-targeted investigative groups. If proven to be correct, this hypothesis could delineate new therapeutic approaches to prevent the progression of diabetic nephropathy.

肾间质纤维化和肾功能衰竭的最新描述 链脲佐菌素糖尿病大鼠模型进行了短暂的时间， 肾缺血提供了一个很好的人类DN模型，并可能揭示 这一现象的潜在发病机制。这种新 观察，无法解释目前流行的超过滤 假设，呼吁改变缺氧诱导机制， DN的进展。事实上，已经证明缺氧本身 一种通过转录控制起作用的基因表达的有效调节剂 和mRNA稳定性来改变多种激素的表达， 生长因子、血管活性化合物和参与 中间代谢在缺氧诱导生长因子中突出 是血管内皮生长因子/血管通透性因子 (VEGF/VPF）。我们假设VEGF的升高 增加肾小球后血管通透性， 糖基化蛋白质的转导触发级联事件， 导致间质纤维化。特别是漏出的糖化血清 另一方面，成分刺激成纤维细胞增殖， 分化成肌成纤维细胞和合成基质蛋白， 而另一方面，这些糖基化产物抑制血管生成， 从而维持慢性缺氧状态。这一假设将是 功能测试（血液动力学参数，组织氧合， 血管生成和血管生成抑制因子的表达，抗VEGF和 VEGF对这些参数的影响），形态学上（糖化蛋白质的作图， 蛋白聚糖、糖蛋白和血管渗透性的其它市场）， 利用细胞生物学方法（分离肾成纤维细胞，共- 内皮细胞与成纤维细胞的培养物，表征参数 糖化基质/血清蛋白对细胞周期的影响 作为基质，基因和基因产物的表达 参与基质合成和降解， 糖化蛋白对这些参数的影响，）细胞生理方法 （在条件下内皮细胞迁移和血管生成潜力 一氧化氮合酶功能障碍或糖化基质的紊乱 蛋白质，血管通透性和血管生成之间的平衡， 受糖化蛋白和VEGF的影响， 通过血管生成促进剂的纤维化）。这个统一假设的证明 内皮依赖性成纤维细胞激活反馈抑制 血管生成，将需要研究几个层次的复杂性-从 从分子和细胞生物学到整个动物生理学， 三个以问题为目标的调查小组的共同努力。如果证明 要想正确，这一假设可能会描绘出新的治疗方法， 预防糖尿病肾病的进展。