P450 EICOSANOIDS AND RENAL FUNCTION IN HYPERTENSION

描述：（改编自研究者摘要）：最近的研究 表明花生四烯酸（AA）的细胞色素P450（CYP 450）代谢产物， 特别是20-HETE，在调节肾小管和 血管功能和长期控制动脉压。期间 在上一个资助期，这名研究人员发现了一个细胞色素基因， P4504 A家族在Dahl S和P4504 B小鼠肾脏中差异表达， 刘易斯大鼠，并与高血压的发展共分离的F2 Dahl S和刘易斯大鼠的杂交。为了进一步探讨该系统在以下方面的作用， 肾功能的控制，他们已经开发（在与博士合作。 Rapp）大鼠的同类品系，其中5号染色体的重叠片段 包括或不包括P4504 A区域的刘易斯大鼠，已经被 通过超过8代的基因渗入Dahl S遗传背景中， 选择性回交育种他们现在建议确定 P4504 A基因在改变肾功能和/或肾损害中起因果作用。 Dahl S大鼠高血压和肾小球硬化的发展：1） 比较血压、肾功能和P4504 A酶的表达 在血压正常的刘易斯的P4504 A等位基因 大鼠已渗入Dahl S遗传背景; 2）确定 选择性肾内阻断20-HETE的形成是否可以“拯救” P4504 A同源Dahl S大鼠的高血压和肾脏表型; 对P4504 A2和4A 3基因的5 ′侧翼区进行克隆和测序， 确定是否存在可以解释这些差异的序列变体 在Dahl S的肾脏外髓质中这些基因的表达中， 和刘易斯大鼠。这些研究将提供重要的新信息， AA的P450代谢产物在肾功能调节中的作用， 确定这一途径是否发挥主要或次要作用， Dahl S大鼠中高血压和/或肾小球疾病的发展。

DESCRIPTION: (Adapted from the Investigator's Abstract): Recent studies have indicated that cytochrome P450 (CYP) metabolites of arachidonic acid (AA), in particular 20-HETE, play a central role in the regulation of renal tubular and vascular function and the long-term control of arterial pressure. During the last funding period, this investigator identified a gene of the cytochrome P4504A family that is differentially expressed in the kidney of Dahl S and Lewis rats and that cosegregates with the development of hypertension in an F2 cross of Dahl S and Lewis rats. To further explore the role of this system in the control of renal function, they have developed (in collaboration with Dr. J. Rapp) congenic strains of rats in which overlapping segments of chromosome 5 of the Lewis rat, that include or exclude the P4504A region, have been introgressed into the Dahl S genetic background by greater than 8 generation of selective back-cross breedings. They now propose to determine whether the P4504A genes play a causal role on altering renal function and/or the development of hypertension and glomerulosclerosis in Dahl S rats by: 1) comparing blood pressure, renal function and the expression of P4504A enzymes in congenic strains of rats in which the P4504A alleles of normotensive Lewis rats have been introgressed into the Dahl S genetic background; 2) determining whether selective intrarenal blockade of the formation of 20-HETE can "rescue" the hypertensive and renal phenotypes in P4504A congenic Dahl S rats; 3) cloning and sequencing the 5'-flanking regions of the P4504A2 and 4A3 genes to determine whether there are sequence variants that can explain the differences in the expression of these genes in the outer medullas of the kidneys of Dahl S and Lewis rats. These studies will provide important new information regarding the role of P450 metabolites of AA in the regulation of renal function and will determine whether this pathway plays a primary or secondary role in the development of hypertension and/or glomerular disease in Dahl S rats.