Abstract P138: Targeted Disruption of Regulated Endocrine Specific Protein ( Resp18 ) in Dahl SS Rats Increases Blood Pressure and Renal Injury

Abstract

Essential hypertension is a complex polygenic trait. To understand the genetics of Blood pressure (BP) control, loci are mapped using populations derived by crossing several rat strains with the genetically hypertensive rat model, the Dahl SS rat (SS) and validated as BP quantitative trait loci (QTL). Genes located within the mapped BP QTLs are candidates as inherited loci controlling BP, but require further proof. One such mapped locus is on rat chromosome 9, wherein the proof for one of the candidate genes Regulated Endocrine Specific Protein-18 ( Resp18 ), as a BP QTL, 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 SS background. As a result of this ZFN mediated disruption, a 7 bp deletion occurred within exon 3 of the Resp18 locus, resulting in a truncated protein with 111aa compared to the full length protein consisting of 175aa. Under a high salt dietary regimen, both systolic and diastolic BP of Resp18 mutant rats were significantly increased compared to SS rats (151±3 vs.170±6mmHg; 116±2vs.129±4mmHg n=10-12, p <0.05). Resp18 mutant rats demonstrated higher proteinuria compared to SS rats (221±14vs.268±14mg of protein/kg body weight/24hr; n=14-25, p <0.05). In vascular reactivity experiment, Resp18 mutant rat mesenteric arteries demonstrated significantly reduced relaxation as compared to SS rats (n=4, p <0.05). An associated decrease in sodium excretion and an increase in glucose excretion were also observed in urine samples of Resp18 mutant rats compared to SS rats (51±7.3vs.27±2.7meq/L/24hr; 10±0.3 vs. 14±1.4mg/dl/24hr,n=5-8, p <0.05).Renal histology examination revealed that Resp18 mutant rat kidneys showed increased fibrosis compared to SS rats. The median survival of Resp18 mutant rats was 259 days, which was significantly lower than the median survival of 309 days for the SS (n=8-16, p <0.05). In conclusion, the data suggest that Resp18 is a gene associated with the development of hypertension, renal disease and increased mortality in the SS rats. Resp18 is a molecule involved in the secretory pathway and thereby, future studies will be conducted to examine the mechanistic links between Resp18 , its function in the secretory pathway and BP regulation.