Benz Kerstin, Amann Kerstin
Contrib Nephrol. 2011;172:139-148. doi: 10.1159/000328695. Epub 2011 Aug 30.
Today diabetic nephropathy is the leading course of end-stage renal disease; the incidence and prevalence of diabetic renal disease is still continuing to increase, particularly in the Western world. Despite improvements in diagnosis and treatment of diabetic nephropathy, only partial renal protection is reached with the current standard therapy regiments, including angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers. Against this background, it is of particular importance to learn more about the pathogenesis of diabetic nephropathy and to find new therapeutic approaches which alone or in combination with standard therapy have the potential to prevent or delay the progression of diabetic nephropathy, thus improving kidney and patient survival. Among others, endothelin (ET) receptor blockers have emerged as a potential therapeutic option that operates on the basis of physiological and pathophysiological effects of endothelin. Of note, the ET system was shown to be involved in hypertension and kidney disease, particularly proteinuric nephropathies, and there is good experimental data indicating a specific role of ET in the pathogenesis and progression of diabetic nephropathy. ET receptor blockers have been shown to be nephroprotective in animal models of type 1 and type 2 diabetes mellitus with the effects partly independent of blood pressure lowering. In patients with hypertension and diabetic nephropathies, the data is controversial and depends on the stage of the disease and the drug used. It was only recently that a large international clinical study (ASCEND) provided evidence for beneficial effects of ET antagonist treatment, i.e. reduction in proteinuria. Due to the premature termination of the study, however, hard endpoints like death could no longer be assessed. Another very recent randomized, double-blind, placebo-controlled trial of subjects with diabetic nephropathy also provided evidence for a specific antiproteinuric effect of the ET receptor antagonist atrasentan on top of an already existing blockade of the renin-angiotensin system. Thus, it appears currently of great scientific and clinical interest to shed some light on the role of the ET system and its blockade in diabetic nephropathy.
如今，糖尿病肾病是终末期肾病的主要病因；糖尿病肾病的发病率和患病率仍在持续上升，尤其是在西方世界。尽管糖尿病肾病的诊断和治疗有所改善，但目前的标准治疗方案（包括血管紧张素转换酶抑制剂和/或血管紧张素受体阻滞剂）仅能提供部分肾脏保护。在此背景下，深入了解糖尿病肾病的发病机制并寻找新的治疗方法尤为重要，这些新方法单独使用或与标准治疗联合使用，有可能预防或延缓糖尿病肾病的进展，从而提高肾脏和患者的生存率。其中，内皮素（ET）受体阻滞剂已成为一种潜在的治疗选择，其作用基于内皮素的生理和病理生理效应。值得注意的是，ET系统被证明与高血压和肾脏疾病有关，尤其是蛋白尿性肾病，并且有充分的实验数据表明ET在糖尿病肾病的发病机制和进展中具有特定作用。在1型和2型糖尿病动物模型中，ET受体阻滞剂已被证明具有肾脏保护作用，其作用部分独立于血压降低。对于高血压和糖尿病肾病患者，相关数据存在争议，且取决于疾病阶段和所用药物。直到最近，一项大型国际临床研究（ASCEND）才提供了ET拮抗剂治疗有益效果的证据，即蛋白尿减少。然而，由于该研究提前终止，死亡等硬终点已无法再进行评估。另一项最近针对糖尿病肾病患者的随机、双盲、安慰剂对照试验也提供了证据，表明在已经存在肾素 - 血管紧张素系统阻断的基础上，ET受体拮抗剂阿曲生坦具有特定的抗蛋白尿作用。因此，目前阐明ET系统及其阻断在糖尿病肾病中的作用具有极大的科学和临床意义。
