Leptin Induces Hypertension Acting on Transient Receptor Potential Melastatin 7 Channel in the Carotid Body.

Abstract

Obesity leads to resistant hypertension and mechanisms are poorly understood, but high plasma levels of leptin have been implicated. Leptin increases blood pressure acting both centrally in the dorsomedial hypothalamus and peripherally. Sites of the peripheral hypertensive effect of leptin have not been identified. We previously reported that leptin enhanced activity of the carotid sinus nerve, which transmits chemosensory input from the carotid bodies (CBs) to the medullary centers, and this effect was abolished by nonselective blockers of Trp (transient receptor potential) channels. We searched our mouse CB transcriptome database and found that the Trpm7 (transient receptor potential melastatin 7) channel was the most abundant Trp channel. To examine if leptin induces hypertension acting on the CB Trpm7. C57BL/6J (n=79), leptin receptor (<i>LepR</i>^<i>b</i>) deficient <i>db/db</i> mice (n=22), and LepRb-EGFP (n=4) mice were used. CB <i>Trpm7</i> and <i>LepR</i>^<i>b</i> gene expression was determined and immunohistochemistry was performed; CB glomus cells were isolated and Trpm7-like current was recorded. Blood pressure was recorded continuously in (1) leptin-treated C57BL/6J mice with intact and denervated CB; (2) leptin-treated C57BL/6J mice, which also received a nonselective Trpm7 blocker FTY720 administered systemically or topically to the CB area; (3) leptin-treated C57BL/6J mice transfected with <i>Trpm7</i> small hairpin RNA to the CB, and (4) <i>Lepr</i>^<i>b</i> deficient obese <i>db/db</i> mice before and after <i>Lepr</i>^<i>b</i> expression in CB. Leptin receptor and Trpm7 colocalized in the CB glomus cells. Leptin induced a nonselective cation current in these cells, which was inhibited by Trpm7 blockers. Leptin induced hypertension in C57BL/6J mice, which was abolished by CB denervation, Trpm 7 blockers, and <i>Trpm7</i> small hairpin RNA applied to CBs. <i>Lepr</i>^<i>b</i> overexpression in CB of <i>Lepr</i>^<i>b</i>-deficient <i>db/db</i> mice demethylated the <i>Trpm7</i> promoter, increased <i>Trpm7</i> gene expression, and induced hypertension. We conclude that leptin induces hypertension acting on Trmp7 in CB, which opens horizons for new therapy.