RORγt Mediates Angiotensin II-Induced Pressor Responses, Microglia Activation, and Neuroinflammation by Disrupting the Blood-Brain Barrier in Rats

Article: RORγt Mediates Angiotensin II-Induced Pressor Responses, Microglia Activation, and Neuroinflammation by Disrupting the Blood-Brain Barrier in Rats

Authors: Yang Yu, Baojian Xue, Lei Tong, Alexander G Bassuk, Alan K Johnson, Shun-Guang Wei

Journal: J Am Heart Assoc. 2025 Mar 4;14(5):e040461

Abstract: Background: 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.

Methods: Rats underwent a 2-week subcutaneous infusion of ANG II, with concurrent daily subcutaneous administration of the RORγt inhibitor digoxin or vehicle.

Results: 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.

Conclusions: 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.

Link to journal online: https://www.ahajournals.org/doi/full/10.1161/JAHA.124.040461