Sex-specific effects of dual ET-1/ANG II receptor (Dear) variants in Dahl salt-sensitive/resistant hypertension rat model

Essential ( polygenic) hypertension is a complex genetic disorder that remains a major risk factor for cardiovascular disease despite clinical advances, reiterating the need to elucidate molecular genetic mechanisms. Elucidation of susceptibility genes remains a challenge, however. Blood pressure ( BP) regulatory pathways through angiotensin II (ANG II) and endothelin-1 (ET-1) receptor systems comprise a priori candidate susceptibility pathways. Here we report that the dual ET-1/ANG II receptor gene ( Dear) is structurally and functionally distinct between Dahl salt-sensitive, hypertensive ( S) and salt-resistant, normotensive ( R) rats. The Dahl S S44/M74 variant is identical to the previously reported Dear cDNA with equivalent affinities for both ET-1 and ANG II, in contrast to Dahl R S44P/M74T variant, which exhibits absent ANG II binding but effective ET-1 binding. The S44P substitution localizes to the ANG II-binding domain predicted by the molecular recognition theory, providing compelling support of this theory. The Dear gene maps to rat chromosome 2 and cosegregates with BP in female F2(RXS) intercross rats with highly significant linkage (LOD 3.61) accounting for 14% of BP variance, but not in male F2(RXS) intercross rats. Altogether, the data suggest the hypothesis that modification of the critical balance between ANG II and ET-1 systems through variant Dear contributes to hypertension susceptibility in female F2(RXS) intercross rats. Further investigations are necessary to corroborate genetic linkage through congenic rat studies, to investigate putative gene interactions, and to show causality by transgenesis and/or intervention. More importantly, the data reiterate the importance of sex-specific factors in hypertension susceptibility.