Narrowing a region on rat chromosome 13 that protects against hypertension in Dahl SS-13^BNcongenic strains

Abstract

RJ. Narrowing a region on rat chromosome 13 that protects against hypertension in Dahl SS-13 BN congenic strains. Am J Physiol Heart Circ Physiol 300: H1530 -H1535, 2011. First published January 21, 2011 doi:10.1152/ajpheart.01026.2010.-Transfer of chromosome 13 from the Brown Norway (BN) rat onto the Dahl saltsensitive (SS) genetic background attenuates the development of hypertension, but the genes involved remain to be identified. The purpose of the present study was to confirm by telemetry that a congenic strain [SS.BN-(D13Hmgc37-D13Got22)/Mcwi, line 5], carrying a 13.4-Mb segment of BN chromosome 13 from position 32.4 to 45.8 Mb, is protected from the development of hypertension and then to narrow the region of interest by creating and phenotyping 11 additional subcongenic strains. Mean arterial pressure (MAP) rose from 118 Ϯ 1 to 186 Ϯ 5 mmHg in SS rats fed a high-salt diet (8.0% NaCl) for 3 wk. Protein excretion increased from 56 Ϯ 11 to 365 Ϯ 37 mg/day. In contrast, MAP only increased to 152 Ϯ 9 mmHg in the line 5 congenic strain. Six subcongenic strains carrying segments of BN chromosome 13 from 32.4 and 38.2 Mb and from 39.9 to 45.8 Mb were not protected from the development of hypertension. In contrast, MAP was reduced by ϳ30 mmHg in five strains, carrying a 1.9-Mb common segment of BN chromosome 13 from 38.5 to 40.4 Mb. Proteinuria was reduced by ϳ50% in these strains. Sequencing studies did not identify any nonsynonymous single nucleotide polymorphisms in the coding region of the genes in this region. RT-PCR studies indicated that 4 of the 13 genes in this region were differentially expressed in the kidney of two subcongenic strains that were partially protected from hypertension vs. those that were not. These results narrow the region of interest on chromosome 13 from 13.4 Mb (159 genes) to a 1.9-Mb segment containing only 13 genes, of which 4 are differentially expressed in strains partially protected from the development of hypertension.Dahl S rats; glomerulus; kidney; renal disease; proteinuria PREVIOUS STUDIES HAVE SHOWN that introgression of chromosome 13 (Chr 13) from the Brown Norway (BN) rat into the saltsensitive (SS) genetic background attenuates the development of hypertension in a SS-13 BN consomic strain (4), but the genes and pathways involved remain to be identified. Our laboratory recently developed 26 overlapping congenic strains and found that 4 different regions of Chr 13 contribute to the lowering of blood pressure (BP) in the SS-13 BN consomic strain (10). BP measured via an arterial catheter after 3 wk on a high-salt diet in one of these congenic strains [SS.BN-(D13Hmgc37-D13Got22)/ Mcwi, line 5] carrying a 13.4-Mb segment of BN Chr 13 between 32.4 and 45.8 Mb was reduced by 30 mmHg (10). This region is distinct from the BP quantitative trait loci (QTL) near the renin gene that was originally identified in an F2 cross and congenic strains derived from Dahl SS and salt-resistant rats (7, 14, 20 -21). This QTL on rat Chr 13 is homologous with a region on human Chr 2 that has be...

Salt Sensitivity of Blood Pressure

“…Study of the role and gene composition of identified quantitative trait loci followed, through the creation of consomic or congenic strains in which putative causative or protective chromosomes or chromosome regions were introgressed from a control to an SS strain or vice versa. With the Dahl-SS strain used as the genetic background, consomic strains harboring chromosome 9 from the Dahl-SR strain 95 ; chromosomes 13, 96 12, 97 104 or chromosomes 15 and 20 of the Brown Norway into the Fawn Hooded rat with salt-induced hypertension. 105 Many of these observations detected sexual dimorphism in the chromosomal effects, and some characterized the mechanism for the antihypertensive effect of protective introgressed chromosomal segments (eg, the segment of chromosome 2 of the Brown Norway strain that improves SS hypertension in Dahl SS reduces inflammation and shifts the balance between CD4 + and regulatory T cells 106 ).…”

“…108 A role for narrower DNA segments was investigated by the creation of congenic strains with introgressed overlapping regions of these chromosomes. A combination of these experiments and the study of differential expression of genes between the congenic and parental strains, detection of nonsynonymous single nucleotide polymorphisms in the regions of interest, and transcriptomic analysis has revealed a number of possible candidate genes, 96,97,100,101,109,110 the majority of which have no previously known cardiovascular regulatory function. However, even with high-resolution substitution mapping, there are usually additional variants flanking a substituted candidate gene, requiring genetic engineering to sort out the significance of the finding.…”

Rab38 Modulates Proteinuria in Model of Hypertension-Associated Renal Disease

“…52 Briefly, 13-week-old rats were anesthetized with 2% isoflurane, and a BP transmitter (PA-C40, DSI) was implanted subcutaneously with the catheter tip secured in the abdominal aorta via the femoral artery. After the 3-day recovery period, BP was measured by radio telemetry in conscious freely moving animals for 3 days, for 3 hours per day.…”

Mapping genetic determinants of kidney damage in rat models

“…72 In further subcongenic breeding experiments, the QTL linked to proteinuria development on RNO13 was narrowed to a 1.9-Mb region, which however also affected BP (Table 3). 73 …”