Journal article
Activation of ADAM17 on glutamatergic neurons selectively promotes sympatho-excitation
Hypertension (Dallas, Tex. 1979), Vol.73(6), pp.1266-1274
06/2019
DOI: 10.1161/HYPERTENSIONAHA.119.12832
PMID: 31006330
Abstract
Chronic activation of the brain renin-angiotensin system contributes to the development of hypertension by altering autonomic balance. Beyond the essential role of Angiotensin-II type 1 receptors, A Disintegrin And Metalloprotease 17 (ADAM17) is also found to promote brain renin-angiotensin system over-activation. ADAM17 is robustly expressed in various cell types within the central nervous system. The aim of this study was to determine whether ADAM17 modulates pre-sympathetic neuronal activity to promote autonomic dysregulation in salt-sensitive hypertension. To test our hypothesis, ADAM17 was selectively knocked down in glutamatergic neurons using Cre-loxP technology. In mice lacking ADAM17 in glutamatergic neurons, the blood pressure increase induced by deoxycorticosterone acetate-salt treatment was blunted. Deoxycorticosterone acetate-salt significantly elevated cardiac and vascular sympathetic drive in control mice, while such effects were reduced in mice with ADAM17 knockdown. This blunted sympatho-excitation was extended to the spleen, with a lesser activation of the peripheral immune system, translating into a sequestration of circulating T cells within this organ, compared to controls. Within the paraventricular nucleus, Angiotensin-II-induced activation of kidney-related pre-sympathetic glutamatergic neurons was reduced in ADAM17 knockdown mice, with the majority of cells no longer responding to Angiotensin-II stimulation, confirming the supportive role of ADAM17 in increasing pre-sympathetic neuronal activity. Overall, our data highlight the pivotal role of neuronal ADAM17 in regulating sympathetic activity, and demonstrate that activation of ADAM17 in glutamatergic neurons leads to a selective increase of sympathetic output, but not vagal tone, to specific organs, ultimately contributing to dysautonomia and salt-sensitive hypertension.
Details
- Title: Subtitle
- Activation of ADAM17 on glutamatergic neurons selectively promotes sympatho-excitation
- Creators
- Jiaxi Xu - Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USAAdrien J.R Molinas - Department of Physiology, Tulane University, New Orleans, LA 70112, USASnigdha Mukerjee - Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USADonald A Morgan - Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USAKamal Rahmouni - Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USAAndrea Zsombok - Department of Physiology, Tulane University, New Orleans, LA 70112, USAEric Lazartigues - Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
- Resource Type
- Journal article
- Publication Details
- Hypertension (Dallas, Tex. 1979), Vol.73(6), pp.1266-1274
- DOI
- 10.1161/HYPERTENSIONAHA.119.12832
- PMID
- 31006330
- ISSN
- 0194-911X
- eISSN
- 1524-4563
- Language
- English
- Date published
- 06/2019
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984071988302771
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