ARTICLE: Leptin Induces Hypertension Acting on Transient Receptor Potential Melastatin 7 Channel in the Carotid Body
AUTHORS: Mi-Kyung Shin, Candela Caballero-Eraso, Yun-Ping Mu, Chenjuan Gu, Bonnie HY Hyeung, Lenise J Kim, Xiao-Ru Liu, Zhi-Juan Wu, Omkar Paudel, Luis E Pichard, Machiko Shirahata, Wan-Yee Tang, James S.K Sham, and Vsevolod Y Polotsky
JOURNAL: Circ Res. 2019 Sep 23. doi: 10.1161/CIRCRESAHA.119.315338. [Epub ahead of print]
Rationale: 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 (CB) to the medullary centers, and this effect was abolished by non-selective blockers of transient receptor potential (Trp) channels. We searched our mouse CB transcriptome database and found that theTrpm7 channel was the most abundant Trp channel.
Objective: To examine if leptin induces hypertension acting on the CB Trpm7.
Methods and Results: C57BL/6J (n=79), leptin receptor (LepRb) deficient db/db mice (n=22), and LepRb-EGFP (n=4) mice were used. CB Trpm7 and LepRb gene expression was determined and immunohistochemistry was performed; CB glomus cells were isolated and Trpm7-like current was recorded. Blood pressure (BP) 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 non-selective Trpm7 blocker FTY720 administered systemically or topically to the CB area; (3) leptin-treated C57BL/6J mice transfected with Trpm7M shRNA to the CB, and (4) Leprb deficient obese db/db mice before and after Leprbexpression in CB. Leptin receptor and Trpm7 co-localized in the CB glomus cells. Leptin induced a non-selective 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 Trpm7 shRNA applied to CBs. Leprb over-expression in CB of Leprb-deficient db/db mice demethylated the Trpm7 promoter, increased Trpm7 gene expression and induced hypertension.
Conclusions: We conclude that leptin induces hypertension acting on Trmp7 in CB, which opens horizons for new therapy.
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