INDUCIBLE DYSPLASTIC NEPHROPATHY IN B2-DEFICENT MICE

描述（改编自申请人的摘要）：缓激肽的合成和 B2受体表达在远端肾单位中瞬时上调 在发展过程中。 初步研究表明，妊娠期高盐 在B2靶向缺失的幼仔中诱导收集系统发育不全 受体的 盐应激B2受体无效幼崽的集合管表现出 EGF受体的表达上调， 凋亡细胞 远端肾单位分化正常进展， 非盐应激的B2受体无效幼仔。 这项建议的目的是 研究缓激肽-B2受体在远端肾单位发育中的作用 在妊娠期盐压力下。 在具体目标1中，产妇的作用 促进盐应激B2表现出的异常肾脏表型的因素 将检查无效幼仔。 妊娠期盐应激 将使用以下方法测试B2无效胚胎中的干扰收集系统发育 定义肾上皮细胞不连续阶段的分子标志物 分化 具体目标2中提出的实验将测试 妊娠期盐应激激活p53介导的卵巢癌的假说 缺乏功能性B2受体。 p53蛋白表达模式及其在胃癌中的意义 下游靶点Bcl-2和Bax将结合原位分析， 检测核DNA片段。 双纯合子B2/p53缺失小鼠 将产生测试的假设，即p53激活发挥作用，在B2 无效异常肾脏表型。 具体目标3侧重于以下方面的作用： EGF受体信号传导在B2无效肾异常的产生。 将分析EGF受体mRNA、蛋白水平和功能活性。 EGF受体功能的部分丧失和获得的影响将是 考察 最终的目标是确定远端肾发生是否紊乱， 与高血压的发展和B2肾功能受损有关 受体缺失小鼠。 这些研究将检查B2受体的作用， 消融对血压的成熟，如果发育应激B2 受体敲除小鼠表现出肾功能受损，B2受体的作用 失活对肾素-血管紧张素系统个体发育的影响，以及 ATII介导B2缺失小鼠的盐敏感性高血压。

DESCRIPTION (Adapted from the Applicant's Abstract): Bradykinin synthesis and B2 receptor expression are transiently up-regulated in the distal nephron during development. Preliminary studies show that gestational high salt induces collecting system dysgenesis in pups with targeted deletion of the B2 receptor. The collecting ducts of salt stressed B2-receptor null pups exhibit up-regulated expression of the EGF-Receptor and an increased number of apoptotic cells. Distal nephron differentiation progresses normally in non-salt stressed B2 receptor null pups. The objective of this proposal is to examine the role of the bradykinin-B2 receptor in distal nephron development during gestational salt stress. In Specific Aim 1, the role of maternal factors in promoting the abnormal renal phenotype exhibited by salt-stressed B2 null pups will be examined. The hypothesis that gestational salt-stress perturbs collecting system development in B2 null embryos will be tested using molecular markers that define discrete stages of renal epithelial differentiation. Experiments proposed in Specific Aims 2 will test the hypothesis that gestational salt stress activates p53 mediated apoptois in the absence of functional B2 receptors. The expression pattern of p53 and its downstream targets, Bcl-2 and Bax, will be analyzed in conjunction with in situ detection of nuclear DNA fragmentation. Double homozygous B2/p53 null mice will be generated to test the hypothesis that p53 activation plays a role in B2 null abnormal renal phenotype. Specific Aim 3 focuses on the role of EGF-receptor signalling in the generation of B2 null renal abnormalities. EGF-receptor mRNA, protein levels and functional activity will be analyzed. The effects of partial loss and gain of EGF-receptor function will be examined. The final aim will determine if disordered distal nephrogenesis is linked to the development of hypertension and impaired renal function in B2 receptor null mice. These studies will examine the effect of B2 receptor ablation on the maturation of blood pressure, if developmentally stressed B2 receptor null mice exhibit impaired renal function, the effects of B2 receptor inactivation on the ontogeny of the renin-angiotensin system, and the role of ATII in mediating salt-sensitive hypertension in B2 null mice.