ANGIOTENSIN II REGULATION OF ENTERIC OXALATE ELIMINATION

在美国，每年大约有一百万例结石疾病被诊断出来。大多数肾结石(80%)是由草酸钙组成的，这种疾病的一个主要危险因素是尿草酸排泄增加。其主要目标是研究和加强草酸在大肠中的清除，在那里草酸可以被底物特异性细菌(Oxalbacter sp.)无害地降解。它们只存在于消化道的这一段。这项建议的具体目标集中在将平衡从肾脏转移到肠道草酸消除所涉及的信号，以及对这种结肠草酸分泌和排泄的调节。从我们最近对慢性肾功能衰竭(CRF)大鼠结肠草酸转运的研究中，出现了三个关键信息。1)。大肠是CRF诱导适应的主要部位，基础草酸吸收被逆转为可被血管紧张素II(Ang II，AT1亚型)受体拮抗剂抑制的分泌通量。2)。在CRF大鼠的肠道中，AT1受体仅在大肠段上调。3)。AT1受体激动剂和拮抗剂对CRF大鼠草酸转运的影响可以在正常支持草酸基础吸收通量的对照组大鼠的体外模拟。综上所述，这些观察表明Ang II在结肠草酸分泌的局部调节中发挥作用。有待检验的工作假说是，肾脏和肠道草酸消除之间的平衡受到结肠AT1受体上调的调节。这项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，以努力模拟人类高草酸/高草酸血症的条件。PR I的目的是研究DIN在分泌草酸的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受体激动剂与启动草酸分泌的运输系统偶联的信号转导途径。拟议研究的结果将为我们对肾脏疾病中草酸盐处理的适应性的基本理解提供重大进展。草酸排泄到大肠的管腔中的潜力，在那里它可以被草酸杆菌酶降解，这提供了一种“蓄水池”机制，如果被利用，可能会对减少高草酸血症、高草酸尿、草酸中毒以及由此导致的各种病理生理和虚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.