Distinct QTLs cosegregate with worse hypertension and renal disease in ovariectomized F2[Dahl S × R]-intercross rats

OBJECTIVES:Salt-sensitive hypertension is highly prevalent in postmenopausal women, with approximately 75% of postmenopausal women found to be hypertensive in the US. Insight from surgical menopause (ovariectomized) patients directly links the loss of endogenous estrogens to salt-sensitive hypertension in previously healthy, salt-resistant women. However, controversial benefit of hormone replacement therapy in postmenopausal women raises the hypothesis that the loss of endogenous estrogens alters genetic susceptibility determinants per se, resulting in hypertension mechanisms beyond correction by hormone replacement. METHODS:We studied ovariectomy-induced changes in hypertension phenotypes and performed a total genome scan for genetic determinants or quantitative trait loci (QTLs), which cosegregate with salt-sensitive hypertension and/or target organ complications in ovariectomized 6-month-old F2[Dahl S × R]-intercross female rats. We used SBP, glomerular injury score (GIS) and relative heart weight (RHW) as quantitative traits. We compared QTLs between ovariectomized and nonovariectomized F2[Dahl S × R]-intercross rats using identical phenotype and genotype characterization. RESULTS:Ovariectomy worsened hypertension and hypertensive nephrosclerosis but reduced RHW. Although some QTLs are common, hence ovarian hormone-independent, distinct BP-QTLs (on chromosomes 9, 13, 20 and X), RHW-QTLs (on chromosomes 1 and 3) and GIS-QTLs (on chromosomes 1 and 8) were detected in ovariectomized F2[Dahl S × R]-intercross female rats. CONCLUSION:Detection of worse hypertension phenotype and distinct QTLs in ovariectomized F2[Dahl S × R]-intercross female rats suggest that distinct genetic determinants underlie postmenopausal hypertension, which are activated, or de-repressed, upon the loss of estrogens.