ANGIOTENSIN II REGULATION OF ENTERIC OXALATE ELIMINATION

在美国，每年大约有100万例结石疾病被诊断出来。大多数肾结石（80%）由草酸钙组成，该疾病的主要危险因素是尿中草酸盐排泄量升高。广泛的目的是研究和加强草酸盐在大肠中的消除，在大肠中，草酸盐可以被专门存在于消化道这一段的底物特异性细菌（草酸杆菌）无害地降解。本建议的具体目的集中在从肾脏到肠道草酸消除的平衡转移所涉及的信号，以及结肠草酸分泌和排泄的调节。我们最近对慢性肾衰竭（CRF）大鼠结肠草酸盐转运的研究得出了三个关键信息。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被血管紧张素II （ANG II，亚型AT1）受体拮抗剂抑制的分泌通量。2）. 在CRF大鼠肠道中，AT1受体仅在大肠段上调。3)。AT1受体的激动和拮抗作用对CRF大鼠体内草酸转运的影响可以在体外模拟正常支持草酸基础吸收通量的对照大鼠中进行。总之，这些观察结果表明，ANG II在结肠草酸盐分泌的局部调节中起作用。需要验证的工作假设是，肾脏和肠道草酸消除之间的平衡是由结肠AT1受体的上调调节的。研究计划分为两个相互关联的部分，包括使用培养细胞模型和各种动物模型来模拟人类高血氧血症/高血氧血症条件。Pr I旨在检测草酸分泌结肠组织中启动结肠T1受体局部上调的信号。在第二部分中，将讨论AT1受体激动作用耦合到启动草酸分泌的运输系统的信号转导途径。所提出的研究结果将为我们对草酸处理肾脏疾病的适应性的基本理解提供重大进展。草酸盐排泄到大肠管腔的潜力，在那里它可以被草酸杆菌酶降解，提供了一个“坑”机制，被利用，可能对减少高氧血症，高草酸血症，草酸病，以及由此产生的各种病理生理和衰弱状况产生重大影响。

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.