Abstract P610: Alterations in 20-HETE Production Contribute to End Organ Damage in Dahl S Rats

Abstract

It is well documented that a sexual dimorphism exists in the regulation of blood pressure in both the human population as well as experimental animal models, such that males have higher blood pressures than females of the same age. While there is a clear disparity in the development of hypertension and progression of renal injury in many rodent models, evidence of a sex difference is lacking in the Dahl S rat. While the current reports present conflicting data, we hypothesize that alterations in CYP450 expression and 20-HETE production contributes to the relative resistance of female Dahl S rats to target organ damage compared to males. Consistent to what we have previously reported, the time course for the development of proteinuria and renal injury were significantly reduced in female Dahl SSJr rats challenged with a high salt diet relative to male rats. In addition, renal cortical 20-HETE production was elevated in female (120.8±4.2 pmol/min/mg) versus male rats (45.1±11.78 pmol/min/mg), while no difference was noted in the outer medulla (19.6±1.8 vs 17.15± 3.9 pmol/min/mg). Introgression of the CYP4A1 gene into the Dahl S genetic background, resulted in significant elevations in 20-HETE production both on low salt and high salt diets. Furthermore the rise in mean arterial pressure was attenuated in CYP4A1 overexpressing rats in both sexes (Δ19mmHg in CYP females vs 61mmg in Dahl S females; 20mmHg in CYP males vs 50mmHg in Dahl S males). Moreover, the degree of glomerular injury was reduced in CYP rats, both male and female, compared to Dahl S rats in response to a high salt diet. Therefore, increases in the CYP gene expression and 20-HETE production prevent the rise in mean arterial pressure and kidney injury in male Dahl S rats. AHA 14SDG20160020