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Articles in PresS, published online ahead of print November 19, 2002
Physiol Genomics, 10.1152/physiolgenomics.00111.2002
Submitted on August 23, 2002
Accepted on November 14, 2002
1 Department of Nephrology and Hypertension, Laboratory for Molecular Medicine and Rat Genome Center, Faculty of Health Sciences, Ben-Gurion University Barzilai Medical Center Campus, Ashkelon, Israel
2 Max-Delbruck Center for Molecular Medicine, Berlin, Germany
3 Department of Clinical Pharmacology and Medicine IV Nephrology, Benjamin Franklin Hospital, Freie University of Berlin, Berlin, Germany
* To whom correspondence should be addressed. E-mail: labmomed{at}bgumail.bgu.ac.il.
We previously detected by linkage analysis in segregating populations derived from crosses between the Sabra hypertension-prone rat (SBH/y) and the hypertension-resistant strain (SBN/y) two QTLs for salt-susceptibility on chromosome 1, with sex specificity: In males SS1a and SS1b and in females SS1b only. To provide support for a functional role of these QTLs in relation to hypertension, we constructed congenic strains by replacing most of or selected segments from chromosome 1 from SBN/y with the homologous chromosomal regions of SBH/y, or reciprocally from SBH/y with segments of SBN/y, leaving the other chromosomes unperturbed. Genetic screening with over 150 microsatellite markers confirmed the homozygosity of the targeted genomic inserts and of the remainder of the genomic background. The phenotype of the congenic strains was tested by salt-loading with DOCA-salt over a 4 week period and measuring blood pressure by tail-cuff (in all animals) or radiotelemetry (in select groups) at baseline and during salt-loading. In the congenic strains in which a chromosomal segment incorporating QTL SS1a from SBN/y was introgressed onto the genomic background of SBN/y, the blood pressure response to salt-loading, as measured by tail-cuff, was decreased by 16 mmHg in both males and females compared to the parental SBH/y; replacing the QTL SS1b reduced the blood pressure response by 30 and 21 mmHg, respectively. In the congenic strains in which both SS1a and SS1b were introgressed from SBN/y onto the genomic background of SBH/y, the reduction in blood pressure was 34 mmHg in males and 38 mmHg in females; these latter results were confirmed by radiotelemetry. When either one or both QTLs together were introgressed from SBH/y onto the SBN/y genomic background, tail-cuff measurements failed to detect an increase in blood pressure above baseline; telemetric measurements in the congenic strains introgressing both QTLs together, however, detected a significant rise in blood pressure after 3 and 4 weeks of salt loading. Neither the origin of the Y chromosome nor the sex of the parental strain had any significant impact on the magnitude of the blood pressure response to salt-loading. We conclude that the congenic rat strains that we constructed for the chromosome 1 QTLs provide functional evidence for the role of gene systems within QTLs SS1a and SS1b in the blood pressure response to salt-loading. The unexpected finding was that QTL SS1a contributes to the hypertensive response also in females. The data indicate the lack of a Y chromosomal effect or of parental imprinting.
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