Targeted disruption of regulated endocrine-specific protein (Resp18) in Dahl SS/Mcw rats aggravates salt-induced hypertension and renal injury
Targeted disruption of regulated endocrine-specific protein (Resp18) in Dahl SS/Mcw rats aggravates salt-induced hypertension and renal injury
复制标题
DOI：
10.1152/physiolgenomics.00008.2018
复制
发表时间：
2018-05-01
影响因子：
4.6
通讯作者：
Joe, Bina
中科院分区：
文献类型：
--
作者：
Kumarasamy, Sivarajan;Waghulde, Harshal;Joe, Bina
高血压是复杂多基因性状的一个典型例子，其受包含被认为负责哺乳动物血压（BP）控制的候选基因的数量性状位点（QTL）的影响。一个这样的定位基因座位于大鼠9号染色体上，其中位置候选基因的证据。调节内分泌特异性蛋白-18（Resp 18）目前不足。为了确定Resp 18作为BP QTL的状态，在Dahl盐敏感（SS）背景下开发了Resp 18的定制靶向基因破坏模型。由于这种锌指核酸酶（ZFN）介导的破坏，在Resp 18基因座的外显子3内发生了7 bp缺失。SS大鼠Resp 18基因位点的靶向破坏降低了其在心脏和肾脏组织中的基因表达，无论其饮食盐水平如何。在高盐饮食方案下，Resp 18（突变）大鼠的收缩压和舒张压均显著高于SS大鼠。与SS大鼠相比，Resp 18（突变体）大鼠表现出肾损伤增加，表现为蛋白尿增加和肾纤维化增加。此外。在高盐饮食方案下，与SS大鼠相比，Resp 18（突变）大鼠的平均存活时间显著缩短。这些发现作为支持Resp 18作为与高血压和肾脏疾病的发展相关的基因的证据。
Hypertension is a classic example of a complex polygenic trait, impacted by quantitative trait loci (QTL) containing candidate genes thought to be responsible for blood pressure (BP) control in mammals. One such mapped locus is on rat chromosome 9, wherein the proof for a positional candidate gene. regulated endocrine-specific protein-18 (Resp18) is currently inadequate. To ascertain the status of Resp18 as a BP QTL, a custom targeted gene disruption model of Resp18 was developed on the Dahl salt-sensitive (SS) background. As a result of this zinc-finger nuclease (ZFN)-mediated disruption, a 7 bp deletion occurred within exon 3 of the Resp18 locus. Targeted disruption of Resp18 gene locus in SS rats decreases its gene expression in both heart and kidney tissues regardless of their dietary salt level. Under a high-salt dietary regimen, both systolic and diastolic BP of Resp18(mutant) rats were significantly increased compared with SS rats. Resp18(mutant) rats demonstrated increased renal damage, as evidenced by higher proteinuria and increased renal fibrosis compared with SS rats. Furthermore. under a high-salt diet regimen, the mean survival time of Resp18(mutant) rats was significantly reduced compared with SS rats. These findings serve as evidence in support of Resp18 as a gene associated with the development of hypertension and renal disease.