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

Mi Kyung Shin, Candela Caballero Eraso, Yun Ping Mu, Chenjuan Gu, Bonnie H.Y. Yeung, Lenise J. Kim, Xiao Ru Liu, Zhi Juan Wu, Omkar Paudel, Luis E. Pichard, Machiko Shirahata, Wan Yee Tang, James S.K. Sham, Vsevolod Y. Polotsky

Research output: Contribution to journalArticle

Abstract

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 (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. 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 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 Trpm7 small hairpin RNA to the CB, and (4) Leprb deficient obese db/db mice before and after Leprb 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 Trpm7 small hairpin RNA applied to CBs. Leprb overexpression 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.

Original languageEnglish (US)
Pages (from-to)989-1002
Number of pages14
JournalCirculation research
Volume125
Issue number11
DOIs
StatePublished - Nov 8 2019

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Carotid Body
Leptin
Hypertension
Inbred C57BL Mouse
Transient Receptor Potential Channels
Leptin Receptors
Small Interfering RNA
Blood Pressure
Gene Expression
Carotid Sinus
Denervation
Transcriptome
Hypothalamus

Keywords

  • carotid body
  • hypertension
  • leptin
  • obesity
  • transient receptor potential channels

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Leptin Induces Hypertension Acting on Transient Receptor Potential Melastatin 7 Channel in the Carotid Body. / Shin, Mi Kyung; Eraso, Candela Caballero; Mu, Yun Ping; Gu, Chenjuan; Yeung, Bonnie H.Y.; Kim, Lenise J.; Liu, Xiao Ru; Wu, Zhi Juan; Paudel, Omkar; Pichard, Luis E.; Shirahata, Machiko; Tang, Wan Yee; Sham, James S.K.; Polotsky, Vsevolod Y.

In: Circulation research, Vol. 125, No. 11, 08.11.2019, p. 989-1002.

Research output: Contribution to journalArticle

Shin, MK, Eraso, CC, Mu, YP, Gu, C, Yeung, BHY, Kim, LJ, Liu, XR, Wu, ZJ, Paudel, O, Pichard, LE, Shirahata, M, Tang, WY, Sham, JSK & Polotsky, VY 2019, 'Leptin Induces Hypertension Acting on Transient Receptor Potential Melastatin 7 Channel in the Carotid Body', Circulation research, vol. 125, no. 11, pp. 989-1002. https://doi.org/10.1161/CIRCRESAHA.119.315338
Shin, Mi Kyung ; Eraso, Candela Caballero ; Mu, Yun Ping ; Gu, Chenjuan ; Yeung, Bonnie H.Y. ; Kim, Lenise J. ; Liu, Xiao Ru ; Wu, Zhi Juan ; Paudel, Omkar ; Pichard, Luis E. ; Shirahata, Machiko ; Tang, Wan Yee ; Sham, James S.K. ; Polotsky, Vsevolod Y. / Leptin Induces Hypertension Acting on Transient Receptor Potential Melastatin 7 Channel in the Carotid Body. In: Circulation research. 2019 ; Vol. 125, No. 11. pp. 989-1002.
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T1 - Leptin Induces Hypertension Acting on Transient Receptor Potential Melastatin 7 Channel in the Carotid Body

AU - Shin, Mi Kyung

AU - Eraso, Candela Caballero

AU - Mu, Yun Ping

AU - Gu, Chenjuan

AU - Yeung, Bonnie H.Y.

AU - Kim, Lenise J.

AU - Liu, Xiao Ru

AU - Wu, Zhi Juan

AU - Paudel, Omkar

AU - Pichard, Luis E.

AU - Shirahata, Machiko

AU - Tang, Wan Yee

AU - Sham, James S.K.

AU - Polotsky, Vsevolod Y.

PY - 2019/11/8

Y1 - 2019/11/8

N2 - 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 (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. 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 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 Trpm7 small hairpin RNA to the CB, and (4) Leprb deficient obese db/db mice before and after Leprb 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 Trpm7 small hairpin RNA applied to CBs. Leprb overexpression 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.

AB - 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 (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. 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 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 Trpm7 small hairpin RNA to the CB, and (4) Leprb deficient obese db/db mice before and after Leprb 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 Trpm7 small hairpin RNA applied to CBs. Leprb overexpression 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.

KW - carotid body

KW - hypertension

KW - leptin

KW - obesity

KW - transient receptor potential channels

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