Summary
A medRxiv preprint reports that surgically induced renovascular hypertension caused white-matter injury in rats, with brain AT1R signaling implicated in the damage. Human cohort analyses linked renal artery stenosis and angiotensin receptor blocker use with MRI measures of white-matter disease.
A medRxiv preprint reports that renovascular hypertension produced brain white-matter injury in rats and implicates angiotensin II signaling through the AT1R receptor in that damage. The researchers also found human cohort associations between renal artery stenosis and greater white-matter hyperintensity (WMH) volume, and between angiotensin receptor blocker (ARB) use and slower WMH progression in some groups.
WMHs are bright areas on certain MRI scans and are a common imaging feature of cerebral small-vessel disease. In this study, the rat experiments connect those imaging changes with damage to myelin—the insulation around nerve fibres—and loss of axons and mature oligodendrocytes, the cells that maintain myelin.
Rat experiments point to a brain blood-vessel pathway
The researchers induced renovascular hypertension in rats using a two-kidney, two-clip procedure, which narrows the arteries supplying the kidneys. About two-thirds of the rats developed WMHs; these expanded between weeks 7 and 9. MRI and tissue analyses also found reduced fractional anisotropy, demyelination, loss of axons and mature oligodendrocytes, and activation of glial cells, which support and respond to changes in brain tissue.
Markers including immunoglobulin G, albumin and fibrinogen leaked from blood vessels in the affected white matter. In tests on brain endothelial cells—the cells lining blood vessels—the hormone angiotensin II impaired barrier function and generated reactive oxygen species through AT1R. Reactive oxygen species are chemically reactive molecules that can contribute to cellular stress.
To test the receptor’s role in the brain, the researchers infused losartan into the brain’s ventricles, the fluid-filled spaces within it. This attenuated white-matter pathology and improved behaviour while blood pressure remained comparably elevated. The result supports a role for brain AT1R signaling in the rat model, separate from a reduction in systemic blood pressure.
Human analyses provide a clinical link, not a treatment test
The preprint reports higher WMH volumes in patients with renal artery stenosis than in those without it: 10.52 mL versus 6.52 mL (P = 0.035). It also analysed WMH progression and antihypertensive drug classes in four cohorts from Korea, the UK and the United States.
ARB use was associated with being in the slowest tertile of annual WMH progression in the Korean CHALLENGE cohort (odds ratio 2.57; 95% confidence interval 1.20–5.61) and among White participants in SPRINT-MIND-MRI (odds ratio 3.52; 95% confidence interval 1.05–12.29). These findings complement the animal results, but the cohort analyses are observational: they identify associations, rather than testing whether ARBs prevent or slow brain injury.
The work is a preprint and has not yet been peer reviewed. Its central mechanistic test used losartan delivered directly into the brain, so it does not establish that routine treatment with an ARB will reproduce the rat result in people. The findings instead identify brain endothelial AT1R signaling as a potential link between kidney-related hypertension and white-matter damage that warrants further clinical investigation.