Brown Norway Chromosome 13 Confers Protection From High Salt to Consomic Dahl S Rat

Abstract

Abstract-Consomic rats (SS.BN13), in which chromosome 13 from normotensive inbred Brown Norway rats from a colony maintained at the Medical College of Wisconsin (BN/Mcw) was introgressed into the background of Dahl salt-sensitive (SS/Mcw) rats, also maintained in a colony at the Medical College of Wisconsin, were bred. The present studies determined the mean arterial pressure (MAP) responses to salt and renal and peripheral vascular responses to norepinephrine and angiotensin II; 24-hour protein excretion and histological analyses were used to assess renal pathology in rats that received a high salt (4% NaCl) diet for 4 weeks. MAP of rats measured daily during the fourth week averaged 170Ϯ3. Key Words: hypertension, sodium dependent Ⅲ rats Ⅲ sodium Ⅲ chromosome 13 Ⅲ blood pressure Ⅲ consomic D ahl salt-sensitive (SS) rats exhibit many of the abnormalities that occur with hypertension in African Americans, 1,2 including blood pressure salt sensitivity, 3,4 insulin resistance, 5 and hyperlipidemia. 6 They have a low renin form of hypertension 3 that is refractory to treatment with converting enzyme inhibitors 7,8 and is effectively treated with diuretics. 7,9 Moreover, these rats rapidly develop severe progressive hypertensive glomerulosclerosis that leads to end-stage renal disease, as is commonly also seen in African Americans with hypertension. 9,10 For these reasons, insights and findings of the studies in SS rats may provide valuable clues to the genetic basis of hypertension and related traits in African Americans.The explosion of genomic resources in the rat has led to remarkable advances in identifying the regions of the rat genome that contain blood pressure quantitative trait loci (QTLs), as reviewed by Hamet et al, 11 Zicha and Kunes,12 and Rapp. 13 We have recently completed a linkage analysis based on an intercross of SS and Brown Norway (BN) salt-insensitive rats in which total genome scans using 238 polymorphic markers, evenly distributed throughout the genome, were scored. All F2 rats (113 males and 99 females) were extensively phenotyped for 239 measured or derived traits. This linkage analysis indicated the existence of a broad range of traits related to pathways of functional importance in hypertension that mapped to 19 chromosomes. 14,15 The development of congenic strains has been used by a number of laboratories, including our own, to confirm and narrow QTL regions of interest. 16,17 Despite the usefulness of congenic rat models in the deconstruction of complex traits and the identification of candidate genes, this work has been hampered by the time and expense involved in producing these informative recombinant rats. Even with the use of markerassisted selection to identify the rats best suited for backcrossing in generations, 18 we have found that the process of developing an inbred congenic strain requires nearly 2 years and 5 to 7 generations of backcrosses to achieve rats that are sufficiently isogenic to make meaningful comparisons.To overcome these limitations, we have been developing ...

Chromosomes 18 and X are quantitative trait loci for nephrotic-range proteinuria in rats

“…Other consomic-based studies of proteinuria have been reported [5,6]. Cowley et al evaluated the role of chromosome 13 in the genetics of hypertension in SS-BN13 consomic rats.…”

“…Cowley et al evaluated the role of chromosome 13 in the genetics of hypertension in SS-BN13 consomic rats. In addition to concluding that rat chromosome 13 contains genes protective against salt-sensitive hypertension, the authors also observed significantly less proteinuria in the SS-13BN rats compared with the SS strain [5]. Yagil et al bred consomic rat strains for Sabra hypertensionprone chromosomes 1 and 17 on a Sabra hypertension-resistant background [6].…”

“…Phenotype and genomic studies of these rats and their parents, performed by PGA and made publicly available, provide an opportunity to single out which chromosomes are loci that are potentially involved in a quantifiable trait of interest, thus providing a resource to discover quantitative trait loci (QTL). QTL provide valuable information regarding the genetic loci underlying complex "continuous" traits such as blood pressure [5,6,7] and proteinuria [6].…”

Use of chromosome substitution strains to identify seizure susceptibility loci in mice

“…Chromosome substitution strain (CSS) analysis is a recently developed method of QTL identification that has been applied successfully to the study of anxiety (Nadeau et al 2000; Singer et al 2004), germ-cell tumors (Matin et al 1999; Youngren et al 2003), hypertension (Cowley et al 2001;Liang et al 2002), response to barbiturates (Stekiel et al 2006), obesity, and sterol levels (Singer et al 2004). Chromosome substitution strains are strains in which a single chromosome from one inbred strain (donor) has been transferred onto a second strain (host) by repeated backcrossing.…”

Renal medullary 11β-hydroxysteroid dehydrogenase type 1 in Dahl salt-sensitive hypertension

“…Programmatic efforts have been undertaken to generate consomic and congenic variants of the SS rat that may facilitate the study of the molecular pathophysiology of salt-sensitive hypertension (5,6,10). These efforts are important since the rat strains commonly used as controls for SS in physiological studies may contain many molecular differences from the SS rat that are unrelated to the hypertension phenotype.…”