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

Abstract

Background: 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 salt-sensitive hypertension, exaggerated proteinuria, high body weight, hyperlipidemia, and elevated insulin-to-glucose ratio. Previous genetic mapping identified quantitative trait loci (QTLs) influencing blood pressure (BP) on rat chromosome 13 (RNO13) in several models of hypertension.

Methods: 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-13BN) and reciprocal consomics by substituting a BN RNO13 with that of LH (BN-13LH). These reciprocal consomic strains, as well as the two parental strains were characterized for BP, metabolic and morphological parameters.

Results: Compared with LH parents, LH-13BN rats showed decreased mean BP (up to -24 mmHg on 2% NaCl in the drinking water), urine proteins and lipids, and increased body weight. Differences between BN-13LH and BN rats were much smaller than those observed between LH-13BN and LH rats, demonstrating the effects of the highly resistant BN genome background. Plasma renin activity was not affected by the substitution of RNO13, despite the significant BP differences.

Conclusion: 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-13BN and the LH make it a powerful model to determine genes and pathways leading to these risk factors for cardiovascular and renal disease.

Figure 1

Time course evolution of body weight in LH (n=10), LH-13^BN (n=10), BN-13^LH (n=9) and BN rats (n=10). ** p<0.01 LH versus BN; †† p<0.01 LH-13^BN versus LH; ‡ p<0.05, ‡‡ p<0.01 BN-13^LH versus BN.

Figure 2

Time course of mean blood pressure (MBP) recorded by radio telemetry in LH rats (n=10), LH-13^BN (n=10), BN-13^LH (n=9) and BN rats (n=10). The telemetric radio-transmitters were implanted at 15 weeks of age. The blood pressure recording periods were indicated by the abbreviation R_X (R₁ for the first recording to R₁₀). Each MBP value corresponds to the average of a 22-h beat-to-beat MBP recording. The values of the first 2 recordings (R₁, R₂) were averaged to obtain the baseline value (R₁₊₂). The top of the graph shows the nature and the chronology of the different salt load (1% and 2% NaCl in drinking water). ** p<0.01 LH versus BN; †† p<0.01 LH-13^BN versus LH; ‡ p<0.05 BN-13^LH versus BN.

Figure 3

Percentage of mean blood pressure increase versus baseline value (R₁₊₂) during high salt load (2% NaCl as drinking water). R₆ and R₇ correspond respectively to 5 and 7 days under high salt load. ** p<0.01 LH versus BN; † p<0.05 LH-13^BN versus LH.