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

Abstract

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(R×S) intercross rats with highly significant linkage (LOD 3.61) accounting for 14% of BP variance, but not in male F2(R×S) 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(R×S) 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.