Leptin Mediates High-Fat Diet Sensitization of Angiotensin II-Elicited Hypertension by Upregulating the Brain Renin-Angiotensin System and Inflammation

Baojian Xue; Yang Yu; Zhongming Zhang; Fang Guo; Terry G Beltz; Robert L Thunhorst; Robert B Felder; Alan Kim Johnson

doi:10.1161/hypertensionaha.115.06736

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Leptin Mediates High-Fat Diet Sensitization of Angiotensin II-Elicited Hypertension by Upregulating the Brain Renin-Angiotensin System and Inflammation

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Leptin Mediates High-Fat Diet Sensitization of Angiotensin II-Elicited Hypertension by Upregulating the Brain Renin-Angiotensin System and Inflammation

Baojian Xue, Yang Yu, Zhongming Zhang, Fang Guo, Terry G Beltz, Robert L Thunhorst, Robert B Felder and Alan Kim Johnson

Hypertension (Dallas, Tex. 1979), Vol.67(5), pp.970-976

05/2016

DOI: 10.1161/hypertensionaha.115.06736

PMCID: PMC4833570

PMID: 27021010

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Abstract

Obesity is characterized by increased circulating levels of the adipocyte-derived hormone leptin, which can increase sympathetic nerve activity and raise blood pressure. A previous study revealed that rats fed a high-fat diet (HFD) have an enhanced hypertensive response to subsequent angiotensin II administration that is mediated at least, in part, by increased activity of brain renin-angiotensin system and proinflammatory cytokines. This study tested whether leptin mediates this HFD-induced sensitization of angiotensin II-elicited hypertension by interacting with brain renin-angiotensin system and proinflammatory cytokine mechanisms. Rats fed an HFD for 3 weeks had significant increases in white adipose tissue mass, plasma leptin levels, and mRNA expression of leptin and its receptors in the lamina terminalis and hypothalamic paraventricular nucleus. Central infusion of a leptin receptor antagonist during HFD feeding abolished HFD sensitization of angiotensin II-elicited hypertension. Furthermore, central infusion of leptin mimicked the sensitizing action of HFD. Concomitant central infusions of the angiotensin II type 1 receptor antagonist irbesartan, the tumor necrosis factor-α synthesis inhibitor pentoxifylline, or the inhibitor of microglial activation minocycline prevented the sensitization produced by central infusion of leptin. RT-PCR analysis indicated that either HFD or leptin administration upregulated mRNA expression of several components of the renin-angiotensin system and proinflammatory cytokines in the lamina terminalis and paraventricular nucleus. The leptin antagonist and the inhibitors of angiotensin II type 1 receptor, tumor necrosis factor-α synthesis, and microglial activation all reversed the expression of these genes. The results suggest that HFD-induced sensitization of angiotensin II-elicited hypertension is mediated by leptin through upregulation of central renin-angiotensin system and proinflammatory cytokines.

Angiotensin II - pharmacology

Cytokines - metabolism

RNA, Messenger - genetics

Diet, High-Fat - adverse effects

RNA, Messenger - analysis

Rats

Male

Reference Values

Renin-Angiotensin System - genetics

Random Allocation

Rats, Sprague-Dawley

Hypertension - physiopathology

Up-Regulation - drug effects

Paraventricular Hypothalamic Nucleus - drug effects

Animals

Cytokines - drug effects

Inflammation - drug therapy

Hypertension - chemically induced

Renin-Angiotensin System - drug effects

Leptin - pharmacology

Blood Pressure Determination

Disease Models, Animal

Inflammation - physiopathology

Details

Title: Subtitle: Leptin Mediates High-Fat Diet Sensitization of Angiotensin II-Elicited Hypertension by Upregulating the Brain Renin-Angiotensin System and Inflammation
Creators: Baojian Xue - From the Departments of Psychological and Brain Sciences (B.X., F.G., T.G.B., R.L.T., A.K.J.), Pharmacology (A.K.J.), and Internal Medicine (Y.Y., R.B.F.), and the François M. Abboud Cardiovascular Research Center (B.X., R.B.F., A.K.J.), University of Iowa, Iowa City; and Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Henan, China (Z.Z.). baojian-xue@uiowa.edu alan-johnson@uiowa.edu
Yang Yu - From the Departments of Psychological and Brain Sciences (B.X., F.G., T.G.B., R.L.T., A.K.J.), Pharmacology (A.K.J.), and Internal Medicine (Y.Y., R.B.F.), and the François M. Abboud Cardiovascular Research Center (B.X., R.B.F., A.K.J.), University of Iowa, Iowa City; and Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Henan, China (Z.Z.)
Zhongming Zhang - From the Departments of Psychological and Brain Sciences (B.X., F.G., T.G.B., R.L.T., A.K.J.), Pharmacology (A.K.J.), and Internal Medicine (Y.Y., R.B.F.), and the François M. Abboud Cardiovascular Research Center (B.X., R.B.F., A.K.J.), University of Iowa, Iowa City; and Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Henan, China (Z.Z.)
Fang Guo - From the Departments of Psychological and Brain Sciences (B.X., F.G., T.G.B., R.L.T., A.K.J.), Pharmacology (A.K.J.), and Internal Medicine (Y.Y., R.B.F.), and the François M. Abboud Cardiovascular Research Center (B.X., R.B.F., A.K.J.), University of Iowa, Iowa City; and Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Henan, China (Z.Z.)
Terry G Beltz - From the Departments of Psychological and Brain Sciences (B.X., F.G., T.G.B., R.L.T., A.K.J.), Pharmacology (A.K.J.), and Internal Medicine (Y.Y., R.B.F.), and the François M. Abboud Cardiovascular Research Center (B.X., R.B.F., A.K.J.), University of Iowa, Iowa City; and Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Henan, China (Z.Z.)
Robert L Thunhorst - From the Departments of Psychological and Brain Sciences (B.X., F.G., T.G.B., R.L.T., A.K.J.), Pharmacology (A.K.J.), and Internal Medicine (Y.Y., R.B.F.), and the François M. Abboud Cardiovascular Research Center (B.X., R.B.F., A.K.J.), University of Iowa, Iowa City; and Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Henan, China (Z.Z.)
Robert B Felder - From the Departments of Psychological and Brain Sciences (B.X., F.G., T.G.B., R.L.T., A.K.J.), Pharmacology (A.K.J.), and Internal Medicine (Y.Y., R.B.F.), and the François M. Abboud Cardiovascular Research Center (B.X., R.B.F., A.K.J.), University of Iowa, Iowa City; and Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Henan, China (Z.Z.)
Alan Kim Johnson - From the Departments of Psychological and Brain Sciences (B.X., F.G., T.G.B., R.L.T., A.K.J.), Pharmacology (A.K.J.), and Internal Medicine (Y.Y., R.B.F.), and the François M. Abboud Cardiovascular Research Center (B.X., R.B.F., A.K.J.), University of Iowa, Iowa City; and Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Henan, China (Z.Z.). baojian-xue@uiowa.edu alan-johnson@uiowa.edu
Resource Type: Journal article
Publication Details: Hypertension (Dallas, Tex. 1979), Vol.67(5), pp.970-976
DOI: 10.1161/hypertensionaha.115.06736
PMID: 27021010
PMCID: PMC4833570
NLM abbreviation: Hypertension
ISSN: 0194-911X
eISSN: 1524-4563
Publisher: United States
Grant note: R01 HL096671 / NHLBI NIH HHS R01 MH080241 / NIMH NIH HHS R01 HL098207 / NHLBI NIH HHS R01 HL073986 / NHLBI NIH HHS HL-073986 / NHLBI NIH HHS P01 HL014388 / NHLBI NIH HHS HL-096671 / NHLBI NIH HHS HL-14388 / NHLBI NIH HHS HL-98207 / NHLBI NIH HHS R01 AG025465 / NIA NIH HHS
Language: English
Date published: 05/2016
Academic Unit: Psychological and Brain Sciences; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Neurology (Pediatrics); Health, Sport, and Human Physiology ; Internal Medicine
Record Identifier: 9984002447302771

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