Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Physiol Genomics. 2011 Jul 14;43(13):808-17. doi: 10.1152/physiolgenomics.00171.2010. Epub 2011 Apr 26.
Impaired regulation of renin in Dahl salt-sensitive rats (SS/JRHsdMcwi, SS) contributes to attenuated angiogenesis in this strain. This study examined angiogenic function and genomic structure of regions surrounding the renin gene using subcongenic strains of the SS and BN/NHsdMcwi (BN) rat to identify important genomic variations between SS and BN involved in angiogenesis. Three candidate regions on Chr 13 were studied: two congenic strains containing 0.89 and 2.62 Mb portions of BN Chr 13 that excluded the BN renin allele and a third strain that contained a 2.02 Mb overlapping region that included the BN renin allele. Angiogenesis induced by electrical stimulation of the tibialis anterior muscle was attenuated in the SS compared with the BN. Congenics carrying the SS renin allele had impaired angiogenesis, while strains carrying the BN renin allele had angiogenesis restored. The exception was a congenic including a region of BN genome 0.4 Mb distal to renin that restored both renin regulation and angiogenesis. This suggests that there is a distant regulatory element in the BN capable of restoring normal regulation of the SS renin allele. The importance of ANG II in the restored angiogenic response was demonstrated by blocking with losartan. Sequencing of the 4.05 Mb candidate region in SS and BN revealed a total of 8,850 SNPs and other sequence variants. An analysis of the genes and their variants in the region suggested a number of pathways that may explain the impaired regulation of renin and angiogenesis in the SS rat.
在 Dahl 盐敏感型大鼠（SS/JRHsdMcwi，SS）中，肾素的调节受损导致该品系的血管生成减弱。本研究使用 SS 和 BN/NHsdMcwi（BN）大鼠的亚纯合系，检查了肾素基因周围区域的血管生成功能和基因组结构，以确定 SS 和 BN 之间与血管生成有关的重要基因组变异。研究了 13 号染色体上的三个候选区域：两个包含 BN 染色体 13 上 0.89 和 2.62 Mb 部分的纯合系，排除了 BN 肾素等位基因，第三个系包含一个包含 BN 肾素等位基因的 2.02 Mb 重叠区域。与 BN 相比，SS 前胫骨肌肉电刺激诱导的血管生成减弱。携带 SS 肾素等位基因的纯合子的血管生成受损，而携带 BN 肾素等位基因的品系的血管生成得到恢复。例外的是携带 BN 基因组中肾素远端 0.4 Mb 区域的纯合子，它恢复了 SS 肾素等位基因的正常调节和血管生成。这表明 BN 中存在一个远距离调节元件，能够恢复 SS 肾素等位基因的正常调节。用洛沙坦阻断 ANG II 证明了其在恢复的血管生成反应中的重要性。对 SS 和 BN 中 4.05 Mb 候选区域的测序共揭示了 8850 个 SNPs 和其他序列变异。对该区域基因及其变异的分析表明，有许多途径可能解释 SS 大鼠肾素和血管生成调节受损的原因。
