ANGIOTENSIN II REGULATION OF ENTERIC OXALATE ELIMINATION

在美国，每年诊断出大约一百万例结石病。大多数肾结石（80%）由草酸钙组成，这种疾病的主要危险因素是尿草酸盐排泄量增加。广泛的目标是研究和增强草酸盐进入大肠的消除，在大肠中草酸盐可以被底物特异性细菌（草酸杆菌属）无害地降解。它们只存在于消化道的这一部分。该提案的具体目标集中在涉及从肾到肠草酸盐消除的平衡转移的信号和结肠草酸盐分泌和排泄的调节上。从我们最近对慢性肾功能衰竭（CRF）大鼠结肠草酸盐转运的研究中，出现了三个关键信息。1）。大肠是CRF诱导适应的主要部位，其中基础草酸盐吸收被逆转为可由血管紧张素II（ANG II，亚型AT 1）受体拮抗剂诱导的分泌通量。2）。在CRF大鼠肠道中，AT 1受体仅在大肠段上调。3）。AT 1受体激动和拮抗作用对CRF大鼠草酸转运的影响可以在正常支持基础草酸吸收通量的对照大鼠中体外模拟。总之，这些观察结果表明，血管紧张素Ⅱ发挥了作用，在结肠草酸分泌的局部调制。待检验的工作假设是肾和肠草酸盐消除之间的平衡通过结肠AT 1受体的上调来调节。该研究计划分为两个相互关联的部分，并涉及使用培养的细胞模型沿着各种动物模型，以模拟人类高尿酸/高血脂状况。Pr Ⅰ的目的是检测在草酸分泌的结肠组织中参与din启动结肠T1受体局部上调的信号。在第二部分中，参与耦合AT 1受体激动剂的运输系统启动草酸分泌的信号转导途径将被解决。这些研究的结果将为我们对肾脏疾病草酸盐处理适应性的基本理解提供重大进展。草酸盐排泄到大肠腔中的潜力（在大肠腔中草酸盐可被草酸酶降解）提供了“贮槽”机制，利用该机制可对减少高尿酸血症、高尿酸血症、草酸盐症以及由此产生的各种病理生理学和衰弱性病症具有显著影响。

Approximately one million cases of stone diseases are diagnosed in the United States every year. Most kidney stones (80%) are comprised of calcium oxalate and a major risk factor in this disease is elevated urinary oxalate excretion. The broad aims are to investigate and enhance elimination of oxalate into the large intestine where it can be innocuously degraded by the substrate-specific bacteria (Oxalobacter sp.) which reside exclusively in this segment of the alimentary tract. The specific aims of this proposal focus on the signals involved in shifting the balance from renal to enteric oxalate elimination and on the modulation of this colonic oxalate secretion and excretion. Three key pieces of information have emerged from our recent studies of colonic oxalate transport in rats with chronic renal failure (CRF). 1). The large intestine is the primary site for the CRF-induced adaptation where basal oxalate absorption is reversed to a secretory flux inhibitable by angiotensin II (ANG II, subtype AT1) receptor antagonists. 2). In CRF rat intestine, AT1 receptors are up-regulated exclusively in the large intestinal segment. 3). The effects of AT1 receptor agonism and antagonism on oxalate transport in the CRF rat can be simulated in vitro in a control rat which normally supports a basal absorptive flux of oxalate. Together, these observations imply that ANG II plays a role in local modulation of colonic oxalate secretion. The working hypothesis to be tested is that the balance between renal and enteric oxalate elimination is modulated by an up- regulation in colonic AT1 receptors. The research plan is divided into two interrelated parts and involves using a cultured cell model along with a variety of animal models created in an effort to simulate human hyperoxaluric/hyperoxalemic conditions. Pr I is aimed at examining the signals involve din initiating the local up-regulation of colonic T1 receptors in oxalate secreting colonic tissues. In Part II, the signaling transduction pathways involved in coupling AT1 receptor agonism to the transport systems initiating oxalate secretion will be addressed. The outcome of the propose studies will provide a significant advance in our fundamental understanding of adaptations in oxalate handling in kidney disease. The potential for oxalate excretion into the lumen of the large intestine, where it can be degraded by Oxalobacter enzymes, provides for a "sump" mechanism which, is exploited, could have significant impact on reducing hyperoxalemia, hyperoxaluria, oxalosis, and the resulting various pathophysiological and debilitating conditions.