Progressive renal and vascular disease: pivotal role of the AT2 receptor

糖尿病和肾脏疾病通常与一系列血管并发症有关。我一直在研究一种特殊的激素系统，被称为肾素血管紧张素系统，它在包括糖尿病在内的各种疾病中促进肾脏和血管并发症。这个系统是一个最终产生一种叫做血管紧张素II的激素的途径，这种激素有许多可能对肾脏和血管有害的作用。这种激素系统的重要性已被证明是有益的影响，特别是对肾脏的药物，阻断这一途径。已经证明血管紧张素II通过两种不同的受体，AT1和AT2亚型起作用。最初，AT1受体被认为介导血管紧张素II的大部分生物学效应。然而，正如我们自己和其他小组所证明的那样，AT2受体可能在介导血管紧张素II的各种作用中发挥作用，特别是在疾病状态下。我们已经确定了这种受体在成人肾脏和血管壁中的表达，在各种疾病状态下可能会上调。AT2受体在糖尿病和许多其他肾脏疾病中的状态尚未得到很好的表征，本提案将通过评估糖尿病的各种损伤部位，包括肾脏和血管树，以全面的方式解决这一问题。这一比例包括调节该受体的不同方法，包括药物阻滞剂和该受体缺失或过度表达的动物模型。这些研究对糖尿病和肾脏并发症的治疗具有潜在的重要意义。AT2受体在糖尿病肾病或其他肾脏疾病中是否具有有益或有害的作用，这些作用在所研究的各个器官中是否存在差异，以及AT2受体拮抗剂本身是否对肾脏和血管疾病高危人群（如糖尿病患者）具有治疗价值，这些都有待确定。

Diabetes and renal disease are commonly associated with a range of vascular complications. I have been investigating a particular hormone system known as the renin-angiotensin system in promoting kidney and vascular complications in various diseases including diabetes. This system is a pathway which ultimately generates a hormone called angiotensin II which has many actions which could be harmful to the kidney and blood vessels. The importance of this hormone system has been demonstrated by the beneficial effects particularly on the kidney of drugs which block this pathway. It has been demonstrated that angiotensin II acts via 2 different receptors, the AT1 and AT2 subtypes. Initially the AT1 receptor was viewed to mediate most of the biological effects of angiotensin II. However, as demonstrated by our own and other groups, the AT2 receptor may play a role in mediating various effects of angiotensin II particularly in disease states. We have identified expression of this receptor in the adult kidney and in the vessel wall which may be upregulated in various disease states. The status of the AT2 receptor is not well characterised in diabetes and many other kidney diseases and this proposal will address this issue in a comprehensive manner by evaluating various sites of injury in diabetes including the kidney and vascular tree. This proporsal includes different approach to moduate this receptor involving drug blockers and animal model where this receptoris either deleted or overexpressed. These studies potentially have major implications for the management of diabetic and renal complications. It remains to be determined if the AT2 receptor confers beneficial or deleterious effects in diabetic nephropathy or other renal diseases, if these effects vary among the various organs to be studied and whether AT2 receptor antagonists may themselves be of therapeutic value in individuals at high risk of kidney and vascular disease such as people with diabetes.