Leptin induces hypertension acting via Transient Receptor Potential channel subfamily M member 7 (Trpm7) in the carotid bodies

Abstract

RATIONALEObesity leads to cardiovascular morbidity and mortality acting via multiple mechanisms including increased prevalence and severity of hypertension. Obesity leads to high levels of leptin which is produced in adipocytes. Increased leptin levels have also been implicated in increased sympathetic activity and the pathogenesis of hypertension in obesity. However, mechanisms for the effects of leptin on blood pressure are unclear. The carotid bodies (CB) express leptin receptor (LepR), but the mechanisms and consequences of leptin action in CB are unknown. We have previously demonstrated that leptin enhances carotid sinus nerve activity in response to hypoxia and this effect is abolished by non‐selective blockers of transient receptor potential (TRP) channels (Shirahata et al., 2015). We have performed a retrospective analysis of the CB transcriptome in mice and found that trpm7 is the most abundant TRP channel. We hypothesized that high levels of circulating leptin signal via LepR in CB leading to hypertension and this effect will be abolished by trpm7 shRNA.METHODS1) We developed a novel technique allowing us to express LepR in mouse CB using an adenoviral vector suspended in Matrigel. LepR deficient male db/db mice were implanted with telemetry in the left femoral artery for blood pressure monitoring. Blood pressure measurements were performed before and after CB infection with adenovirus carrying the LepR gene (Ad‐LepR, n=5) or luciferase (control, Ad‐Laz, n=6); 2) Male C57BL/6J mice (n=13) were implanted with telemetry for blood pressure monitoring at baseline, during leptin infusion (120ug/day for 3 days via a SC pump) with adenoviral vector which contained trpm7 shRNA (N=6) or control shRNA (N=7);RESULTS1) LepR expression in CB of db/db mice significantly increased mean arterial pressure by 6 mmHg during the day and by 13 mmHg during at night (p < 0.005), whereas CB infection with a control virus had no effect (p=0.585). 2) In C57BL/6J mice, leptin infusion increased mean arterial pressure by 11 mm Hg during the day (p<0.001) and by 15 mm Hg at night (p <0.001). Adenoviral trpm7 shRNA completely abolished leptin‐induced hypertension (p < 0.001).CONCLUSIONSLeptin increases blood pressure acting via LepR in the CB. Leptin‐induced hypertension is abolished by trpm7 shRNA suggesting that leptin may act via TRPM7.Support or Funding InformationHL 133100, HL128970This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.