VASCULAR PERMEABILITY IN DIABETIC NEPHROPATHY

最近对肾间质纤维化和肾功能衰竭的描述 链脲佐菌素对大鼠短期糖尿病模型的影响 肾缺血提供了一种很好的人类糖尿病肾病模型，并可能对 这一现象的潜在致病机制。如此新奇 观察到的，不能用目前流行的超滤解释 假说，呼吁交替的低氧诱导机制 糖尿病肾病的进展。事实上，事实已经证明，缺氧本身就是 一种强大的基因表达调控因子，通过转录调控发挥作用 和信使核糖核酸的稳定性来改变多种激素的表达， 涉及的生长因子、血管活性化合物和分子 中间代谢。在低氧诱导的生长因子中表现突出 是血管内皮生长因子/血管通透性因子 (血管内皮生长因子/血管内皮生长因子)。我们假设升高的血管内皮细胞生长因子 产生，肾小球后血管通透性增加和 糖基化蛋白的转导触发了一系列事件，这些事件 导致间质纤维化。具体地说，糖化血清 另一方面，成分可以刺激成纤维细胞的增殖， 分化为肌成纤维细胞和合成基质蛋白， 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(血流动力学参数、组织氧合、 血管生成和血管抑制因子的表达及抗血管内皮生长因子和血管内皮生长因子的作用 这些参数上的血管内皮生长因子)、形态(糖化蛋白的图谱， 蛋白多糖、糖蛋白和其他血管通透性市场)， 使用细胞生物学的方法(分离肾成纤维细胞，共培养 内皮细胞与成纤维细胞的培养，参数表征 细胞周期及其糖化基质/血清蛋白的修饰 利用作为底物的基因和基因产物的表达 参与基质合成和降解及其影响 糖化蛋白质对这些参数的影响，)细胞生理途径 (条件下内皮细胞迁移和血管生成潜能 功能失调的一氧化氮合酶或糖化基质的紊乱酶系 蛋白质，血管通透性和血管生成之间的平衡 受糖化蛋白和血管内皮生长因子的影响，以及可能的解决方案 血管生成促进剂的纤维化)。这一统一假设的证明 内皮依赖性成纤维细胞激活反馈性抑制 血管生成，将需要对几个级别的复杂性进行研究-从 分子和细胞生物学到整个动物生理学-并保证 三个针对问题的调查小组的共同努力。如果经过验证 准确地说，这一假说可以描绘出新的治疗方法。 以防止糖尿病肾病的进展。

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.