Renovascular hypertension drives ischemic white matter injury via brain endothelial AT1R signaling
- 1Ajou University School of Medicine
Abstract
BACKGROUNDWhite matter hyperintensities (WMHs), the principal imaging manifestation of cerebral small vessel disease, lack an animal model that produces pathology of sufficient magnitude to validate potential therapeutics. We characterized white matter (WM) degeneration in a renovascular hypertension (RVH) rat model, interrogated its mechanism, and tested its relevance in patients.
METHODSRVH was induced by two-kidney, two-clip surgery and assessed by T2-weighted and diffusion MRI, myelin and axonal histology, and blood-brain barrier (BBB) leakage markers. The influence of angiotensin II (Ang II) on barrier function in brain endothelial cells was examined using transendothelial electrical resistance and reactive oxygen species (ROS) assays. Losartan was infused intracerebroventricularly to block brain AT1R (Ang II type 1 receptor) without systemic blood pressure reduction. WMH burden was compared between patients with and without renal artery stenosis, and WMH progression across antihypertensive classes was assessed in the CHALLENGE (Korea), MSS2 (UK), LBC1936 (UK), and SPRINT-MIND-MRI (US) cohorts.
RESULTSApproximately two-thirds of RVH rats developed WMHs that expanded between 7 and 9 weeks, accompanied by reduced fractional anisotropy, demyelination, axonal and mature oligodendrocyte loss, and glial activation. IgG, albumin, and fibrinogen leakage was confined to affected WM. Ang II impaired endothelial barrier function and generated ROS through AT1R. Intracerebroventricular losartan attenuated WM pathology and improved behavior while blood pressure remained comparably elevated. Patients with renal artery stenosis had higher WMH volumes (10.52 versus 6.52 mL; P = 0.035). Angiotensin receptor blocker use was associated with the slowest tertile of annual WMH progression in the Korean cohort (OR, 2.57 [95% CI, 1.20-5.61]) and among White participants in SPRINT-MIND-MRI (OR, 3.52 [95% CI, 1.05-12.29]).
CONCLUSIONSRVH produces prominent ischemic WM degeneration driven by AT1R signaling, identifying a blood pressure-independent therapeutic target with corroborating clinical evidence.
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BibTeX
@misc{jin2026renovascular,
title = {{Renovascular hypertension drives ischemic white matter injury via brain endothelial AT1R signaling}},
author = {X. Jin and H. Kim and H. Jung and Y. Cui and S. S. Singh and H. G. Seo and S. E. Kim and H. W. Lee and T. D. Farr and J. M. Wardlaw and S. R. Cox and S. H. Choi and M. d. C. Valdes Hernandez and J. Y. Choi and B. G. Kim},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.15.26365689},
url = {https://www.medrxiv.org/content/10.64898/2026.10.15.26365689v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Renovascular hypertension drives ischemic white matter injury via brain endothelial AT1R signaling
AU - X. Jin
AU - H. Kim
AU - H. Jung
AU - Y. Cui
AU - S. S. Singh
AU - H. G. Seo
AU - S. E. Kim
AU - H. W. Lee
AU - T. D. Farr
AU - J. M. Wardlaw
AU - S. R. Cox
AU - S. H. Choi
AU - M. d. C. Valdes Hernandez
AU - J. Y. Choi
AU - B. G. Kim
PY - 2026
DA - 2026/10/15
PB - medRxiv
DO - 10.64898/2026.10.15.26365689
UR - https://www.medrxiv.org/content/10.64898/2026.10.15.26365689v1
AB - BACKGROUNDWhite matter hyperintensities (WMHs), the principal imaging manifestation of cerebral small vessel disease, lack an animal model that produces pathology of sufficient magnitude to validate potential therapeutics. We characterized white matter (WM) degeneration in a renovascular hypertension (RVH) rat model, interrogated its mechanism, and tested its relevance in patients. METHODSRVH was induced by two-kidney, two-clip surgery and assessed by T2-weighted and diffusion MRI, myelin and axonal histology, and blood-brain barrier (BBB) leakage markers. The influence of angiotensin II (Ang II) on barrier function in brain endothelial cells was examined using transendothelial electrical resistance and reactive oxygen species (ROS) assays. Losartan was infused intracerebroventricularly to block brain AT1R (Ang II type 1 receptor) without systemic blood pressure reduction. WMH burden was compared between patients with and without renal artery stenosis, and WMH progression across antihypertensive classes was assessed in the CHALLENGE (Korea), MSS2 (UK), LBC1936 (UK), and SPRINT-MIND-MRI (US) cohorts. RESULTSApproximately two-thirds of RVH rats developed WMHs that expanded between 7 and 9 weeks, accompanied by reduced fractional anisotropy, demyelination, axonal and mature oligodendrocyte loss, and glial activation. IgG, albumin, and fibrinogen leakage was confined to affected WM. Ang II impaired endothelial barrier function and generated ROS through AT1R. Intracerebroventricular losartan attenuated WM pathology and improved behavior while blood pressure remained comparably elevated. Patients with renal artery stenosis had higher WMH volumes (10.52 versus 6.52 mL; P = 0.035). Angiotensin receptor blocker use was associated with the slowest tertile of annual WMH progression in the Korean cohort (OR, 2.57 [95% CI, 1.20-5.61]) and among White participants in SPRINT-MIND-MRI (OR, 3.52 [95% CI, 1.05-12.29]). CONCLUSIONSRVH produces prominent ischemic WM degeneration driven by AT1R signaling, identifying a blood pressure-independent therapeutic target with corroborating clinical evidence.
ER -