Exppression and function of two paracrine hormonal regulation of nephron

产品说明：（改编自申请人的摘要）肾单位管腔中的肾素-血管紧张素系统（RAS）和激肽释放酶-激肽系统（KKS）的表达必须通过肾对钠和水的处理影响循环体内平衡。 将使用小鼠作为实验模型来测试关于这些系统的调节和功能的假设。 他们提出，旁分泌RAS沿着整个肾单位发挥作用，涉及近端小管（PT）来源的血管紧张素原（AGT）和连接小管（CNT）合成和分泌的肾素。 在随后的工作中，他们发现肾素和组织激肽释放酶由CNT的相同细胞表达。 主要假设是肾小管RAS和KKS在最终钠排泄的调节中发挥密切相关的旁分泌功能;这两个系统此后被称为肾素-激肽释放酶系统（RKS）。 他们将测试关于以下方面的特定假设：（1）膳食钠对RKS激素前体的调节，（2）对膳食盐反应的菌株特异性差异的遗传基础，以及（3）PT血管紧张素原表达和遗传背景在动脉压（AP）调节中的意义。 这些激素成分与肾脏对钠和水的处理之间的关系将通过以下实验进行测试：（1）钠平衡将被膳食钠的操纵与血浆体积的一致或不一致改变所破坏;（2）沿着肾单位的各个部位的节段性钠和液体递送将通过用利尿剂选择性改变重吸收来操纵;（3）肾小管RKS在肾钠处理中的意义将通过特异性药理学抑制来探讨。 阿米洛利依赖性的钠的味道和CNT的肾素表达一致的菌株的变化表明，在一个或多个基因参与或调节钠进入上皮细胞的菌株之间的遗传差异的假设。他们建议通过选择菌株的回交中的连锁分析来绘制这样的基因，并根据候选基因策略来鉴定因果突变。 为了检验PT血管紧张素原和遗传背景对基线AP的显著性，将在两种不同背景下表达1 - 3个AGT基因的转基因动物中检查肾小管RKS对膳食钠持续改变的反应。

DESCRIPTION: (Adapted from the applicant's abstract) Expression of both a renin-angiotensin system (RAS) and a kallilrein-kinin system (KKS) in tubular lumen of the nephron must impact on circulatory homeostasis through renal handling of sodium and water. Hypotheses regarding the regulation and function of these systems will be tested using the mouse as an experimental model. They have proposed that a paracrine RAS operates along the entire nephron that involves angiotensinogen (AGT) of proximal tubule (PT) origin and renin synthesized and secreted by connecting tubule (CNT). In subsequent work, they have found that renin and tissue kallikrein are expressed by the same cells of CNT. The main hypothesis is that tubular RAS and KKS exert closely interrelated paracrine functions in the regulation of final sodium excretion; these two systems are thereafter referred to as renin- kallikrein system (RKS). They will test specific hypotheses concerning (1) the regulation of hormone precursors of the RKS by dietary sodium, (2) the genetic basis for strain-specific differences in response to dietary salt, and (3) the significance of both PT angiotensinogen expression and genetic background in arterial pressure (AP) regulation. The relationship between these hormonal components and renal handling of sodium and water will be tested through the following experiments: (1) sodium balance will be disrupted by manipulations of dietary sodium with concordant or discordant alteration of plasma volume; (2) segmental sodium and fluid delivery at various sites along the nephron will be manipulated by selective alteration of reabsorption with diuretics; (3) the significance of the tubular RKS in renal sodium handling will be probed by specific pharmacological inhibition. Concordant strain variation in the amiloride-dependance of both sodium taste and CNT renin expression suggest the hypothesis of a genetic difference among strains in one or more genes involved in or regulated by sodium entry in epithelial cells. They propose to map such genes by linkage analysis in backcrosses of select strains and to identify the causal mutations following a candidate gene strategy. To test the significance of PT angiotensinogen and genetic background for baseline AP, the response of the tubular RKS to sustained alterations of dietary sodium will be examined in transgeneic animals expressing one to three AGT genes in two distinct backgrounds.