Implication of chromosome 13 on hypertension and associated disorders in Lyon hypertensive rats

Abstract

Hypertension and associated disorders are major risk factors for cardiovascular disease. The Lyon Hypertensive rat (LH) is a genetically hypertensive strain that exhibits spontaneous and saltsensitive hypertension, exaggerated proteinuria, high body weight, hyperlipidemia and elevated insulin-to-glucose ratio. Previous genetic mapping identified Quantitative Trait Loci (QTL) influencing blood pressure on chromosome 13 (RNO13) in several models of hypertension. To study the effects of a single chromosome on the mapped traits, we generated consomic strains by substituting LH RNO13 with that of the normotensive Brown Norway (BN) strain (LH-13 BN ) and reciprocal consomics by substituting a BN RNO13 with that of LH (BN-13 LH ). These reciprocal consomic strains, as well as the two parental strains were characterized for blood pressure, metabolic and morphological parameters. Compared to LH parents, LH-13 BN rats showed decreased mean blood pressure (up to −24 mmHg on 2%NaCl in the drinking water), urine proteins and lipids, and increased body weight. Differences between BN-13 LH and BN rats are much smaller than those observed between LH-13 BN and LH rats, demonstrating the effects of the highly resistant BN genome background. Plasma renin activity is not affected by the substitution of RNO13, despite the significant blood pressure differences.The present work demonstrates that RNO13 is a determinant of BP, proteinuria, and plasma lipids in the LH rat. The distinct phenotypic differences between the consomic LH-13 BN and the LH make it a powerful model to determine genes and pathways leading to these risk factors for cardiovascular and renal disease.

Mapping genetic determinants of kidney damage in rat models

“…Gilibert et al 127 confirmed in consomic studies using BN as a reference strain in an LH-13 BN consomic strain, in which BN/ NHsdMcwi-RNO13 was transferred into the LH background, the functional relevance of the RNO13 carrying BP-QTL (Table 2). Interestingly, the LH-13 BN consomic strain exhibits a 50% reduction in proteinuria in LH-13 BN compared with LH.…”

“…127 In contrast, reciprocal introgression of LH-RNO13 into the BN background is not capable of inducing a proteinuria phenotype in the consomic strain BN-13 LH . 127 …”

“…Interestingly, the LH-13 BN consomic strain exhibits a 50% reduction in proteinuria in LH-13 BN compared with LH. 127 However, it could be not clarified whether the amelioration in proteinuria depends on the lower BP observed in the congenic strain or whether genetic factors on RNO13 control the proteinuria development. 127 In contrast, reciprocal introgression of LH-RNO13 into the BN background is not capable of inducing a proteinuria phenotype in the consomic strain BN-13 LH .…”

“…16,122,123 Strain characteristics LH rats demonstrate mild spontaneous, salt-sensitive hypertension, proteinuria and albuminuria and exhibit several features common to the human metabolic syndrome including dyslipidemia, insulin resistance and glucose intolerance. [124][125][126][127] Cosegregation and linkage analyses Two linkage analyses were performed by using a male LH Â LN F2 population for BP, anthropometry, renal, metabolic and endocrine phenotypes. 124,126 For the renal phenotype, data QTL were demonstrated for creatinine levels on RNO1, RNO2 and RNO17 and for kidney weight phenotypes on RNO1-RNO3, RNO10 and RNO17, while no linkage for proteinuria, albuminuria or structural kidney damages was reported (Table 1).…”

Rat Chromosome 8 Confers Protection against Dyslipidemia Caused by a High-Fat/ Low-Carbohydrate Diet

“…This panel is used as a genetic tool to determine chromosomes that harbor genes involved in complex traits [19], and has been used specifically to identify chromosomes involved in hypertension [20-22]. Other panels, such as the Lyon hypertensive (LH) consomic strain (LH-17(BN)) has shown utility for traits involved in metabolic syndrome [23].…”