Journal article
RORγt Mediates Angiotensin II-Induced Pressor Responses, Microglia Activation, and Neuroinflammation by Disrupting the Blood-Brain Barrier in Rats
Journal of the American Heart Association, Vol.14(5), e040461
03/04/2025
DOI: 10.1161/JAHA.124.040461
PMCID: PMC12132782
PMID: 40008506
Appears in UI Libraries Support Open Access
Abstract
The RORγt (nuclear receptor retinoid-related orphan receptor γt) has been identified as a master transcription factor critical for the differentiation of T helper 17 cells, the primary source of IL-17A (interleukin-17A). We previously demonstrated that IL-17A promotes neuroinflammation and sympathetic excitation, contributing to cardiac dysfunction in heart failure and angiotensin II (ANG II)-induced hypertension. The present study sought to determine whether inhibiting RORγt, thereby reducing IL-17A production, could attenuate microglial activation, neuroinflammation, and sympathetic excitation by preserving the integrity of the blood-brain barrier (BBB) in ANG II-induced hypertensive rats.
Rats underwent a 2-week subcutaneous infusion of ANG II, with concurrent daily subcutaneous administration of the RORγt inhibitor digoxin or vehicle.
Compared with controls, ANG II-infused rats exhibited elevated IL-17A levels in both the periphery and brain, along with increased blood pressure and sympathetic tone-effects that were significantly attenuated by inhibiting RORγt with digoxin. ANG II-infused rats also displayed heightened BBB permeability, decreased expression of the BBB regulator Mfsd2a (major facilitator superfamily domain-containing protein 2a), increased caveolar transcytosis, and degradation of tight junction proteins in BBB endothelial cells within the hypothalamic paraventricular nucleus, a key autonomic regulatory brain center, all of which were alleviated by digoxin. Additionally, ANG II-infused rats showed marked microglial activation and elevated expression of proinflammatory cytokines within the paraventricular nucleus, both of which were mitigated by digoxin.
These findings suggest that RORγt inhibition reduces neuroinflammation and sympathetic activation to ameliorate ANG II-induced hypertension, likely by mitigating IL-17A-induced BBB disruption and microglial activation in the paraventricular nucleus.
Details
- Title: Subtitle
- RORγt Mediates Angiotensin II-Induced Pressor Responses, Microglia Activation, and Neuroinflammation by Disrupting the Blood-Brain Barrier in Rats
- Creators
- Yang Yu - University of IowaBaojian Xue - University of IowaLei Tong - University of IowaAlexander G Bassuk - University of IowaAlan K Johnson - University of IowaShun-Guang Wei - Iowa City VA Medical Center
- Resource Type
- Journal article
- Publication Details
- Journal of the American Heart Association, Vol.14(5), e040461
- DOI
- 10.1161/JAHA.124.040461
- PMID
- 40008506
- PMCID
- PMC12132782
- NLM abbreviation
- J Am Heart Assoc
- ISSN
- 2047-9980
- eISSN
- 2047-9980
- Publisher
- Wiley
- Grant note
- National Heart, Lung, and Blood Institute of the National Institutes of Health: R01 HL- 139521, HL- 155091 Tross Family Epilepsy FundNational Institutes of Health: 5P50HD103556-03, 5R01EY030151-05, 5R01EY031952-04, 5R01NS127428-02
This work was supported by research grants from National Heart, Lung, and Blood Institute of the National Institutes of Health under award numbers R01 HL- 139521 & HL- 155091 (to S.- G. Wei). Alexander G. Bassuk was funded by the Tross Family Epilepsy Fund and by National Institutes of Health grants 5P50HD103556-03, 5R01EY030151-05, 5R01EY031952-04, and 5R01NS127428-02. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
- Language
- English
- Electronic publication date
- 02/26/2025
- Date published
- 03/04/2025
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Psychological and Brain Sciences; Iowa Neuroscience Institute; Cardiovascular Medicine; Neuroscience and Pharmacology; Neurology (Pediatrics); Internal Medicine
- Record Identifier
- 9984795378902771
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