Targeted disruption of regulated endocrine-specific protein (Resp18) in Dahl SS/Mcw rats aggravates salt-induced hypertension and renal injury

Abstract

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 Resp18mutant rats were significantly increased compared with SS rats. Resp18mutant 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 Resp18mutant 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.