Dissection of Chromosome 18 Blood Pressure and Salt-Sensitivity Quantitative Trait Loci in the Spontaneously Hypertensive Rat

Abstract

Hypertension in humans and experimental models has a strong hereditary basis, but identification of causative genes remains challenging. Quantitative trait loci (QTLs) for hypertension and salt sensitivity have been reported on rat chromosome 18. We set out to genetically isolate and prioritise genes within the salt sensitivity and hypertension QTLs on the spontaneously hypertensive rat (SHR) chromosome 18, by developing and characterising a series of congenic strains derived from the SHR and normotensive Brown Norway (BN) rat strains. The SHR.BN-D18Rat113/D18Rat82 (SHR-18) congenic strain exhibits significantly lower blood pressure and is salt-resistant compared to SHR. Transplantation of kidneys from SHR-18 donors into SHR recipients is sufficient to attenuate increased blood pressure but not salt sensitivity. Derivation of congenic sublines allowed separation of salt sensitivity from hypertension QTL regions. Renal expression studies with microarray and Solexa-based sequencing in parental and congenic strains identified four differentially expressed genes within the hypertension QTL region, one of which is an unannotated transcript encoding a previously undescribed, small non-coding RNA. Sequencing selected biological candidate genes within the minimal congenic interval revealed a non-synonymous variant in SHR Transcription factor 4. The minimal congenic interval is syntenic to a region of human chromosome 18 where significant linkage to hypertension was observed in family-based linkage studies. These congenic lines provide reagents for identifying causative genes that underlie the chromosome 18 SHR QTLs for hypertension and salt sensitivity. Candidate genes identified in these studies merit further investigation as potentially causative hypertension genes in SHR and human hypertension.

Overexpression of VEGF-C attenuates chronic high salt intake-induced left ventricular maladaptive remodeling in spontaneously hypertensive rats

“…VEGF-C AND HYPERTENSIVE LV REMODELING (15,33,55). Long-term HS intake can increase the expression of transforming growth factor ␤ and activate the renninangiotensin-aldosterone system, which promotes myocardial fibrosis and cardiac dysfunction (28,49).…”

Online tools for understanding rat physiology

“…Congenic strains have the additional power of narrowing the list of possible candidate genes and prioritize genes for further study. This strategy has been successfully used to separate salt-sensitivity and hypertension quantitative trail loci (QTLs) on chromosome 18 in the spontaneously hypertensive rat (SHR) [10]. Another research team developed congenic strains to further dissect four blood pressure QTLs on chromosomes 2, 4 and 16 in the SHR.…”

Vascular responses in aortic rings of a consomic rat panel derived from the Fawn Hooded Hypertensive strain

“…For example, QTLs have been reported on chromosome 16 for salt sensitivity of systolic blood pressure in an SHR ϫ BN cross (1); for blood pressure in congenic SS rats carrying Lewis alleles (45); for sex-specific renal disease in stroke-prone SHR (21); and for blood pressure and metabolic disease in a cross of Lyon hypertensive ϫ Lyon normotensive rats (5). In the case of chromosome 18, QTLs have been reported for hypertension and salt sensitivity in an SHR ϫ BN cross (27) and for blood pressure in an F 2 hybrid cross of SHR and normotensive BB/OK spontaneously diabetic rats (28).…”