Inhibition of the renin-angiotensin system causes concentric hypertrophy of renal arterioles in mice and humans

Abstract

Inhibitors of the renin-angiotensin system (RAS) are widely used to treat hypertension. Using mice harboring fluorescent cell lineage tracers, single-cell RNA-Seq, and long-term inhibition of RAS in both mice and humans, we found that deletion of renin or inhibition of the RAS leads to concentric thickening of the intrarenal arteries and arterioles. This severe disease was caused by the multiclonal expansion and transformation of renin cells from a classical endocrine phenotype to a matrix-secretory phenotype: the cells surrounded the vessel walls and induced the accumulation of adjacent smooth muscle cells and extracellular matrix, resulting in blood flow obstruction, focal ischemia, and fibrosis. Ablation of the renin cells via conditional deletion of β 1 integrin prevented arteriolar hypertrophy, indicating that renin cells are responsible for vascular disease. Given these findings, prospective morphological studies in humans are necessary to determine the extent of renal vascular damage caused by the widespread use of inhibitors of the RAS.

Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting

“…However, when homeostasis fails to be restored (e.g., due to chronic stimuli such as RAS blockade, hypotension, and salt depletion), the progressive transformation of arteriolar cells occurs constantly and the renin program is inappropriately overactivated, leading to concentric vascular hypertrophy ( Gomez and Sequeira-Lopez, 2018 ; Guessoum et al, 2021 ; Sequeira-Lopez and Gomez, 2021 ). Hence, the deletion of RAS genes or chronic RAS inhibition in both mice and humans causes concentric arterial and arteriolar hypertrophy accompanied by the accumulation of renin cells ( Oka et al, 2017 ; Guessoum et al, 2021 ; Watanabe et al, 2021 ). Ablation of renin cells by either conditional β 1-integrin deletion or diphtheria toxin prevents this phenomenon ( Pentz et al, 2004 ; Watanabe et al, 2021 ), indicating that renin cells are responsible for vascular hypertrophy.…”

“…Hence, the deletion of RAS genes or chronic RAS inhibition in both mice and humans causes concentric arterial and arteriolar hypertrophy accompanied by the accumulation of renin cells ( Oka et al, 2017 ; Guessoum et al, 2021 ; Watanabe et al, 2021 ). Ablation of renin cells by either conditional β 1-integrin deletion or diphtheria toxin prevents this phenomenon ( Pentz et al, 2004 ; Watanabe et al, 2021 ), indicating that renin cells are responsible for vascular hypertrophy.…”

Flexible and multifaceted: the plasticity of renin-expressing cells

“…The renin + cells adapt a more VSMC-like phenotype with upregulated expression of α-SMA, SM-MHC, and calponin-1, while maintaining renin expression. Based on these findings, further studies are needed to determine more precisely the morphologic and functional consequences of RASi treatment to be able to balance its positive and negative effects in the future [72,114].…”

Four-Year Report on Renal Outcomes Following Elective Withdrawal of Long-Term RAAS Blockade in a Cohort of Patients with Otherwise Inexplicable New-Onset and Progressive Acute Kidney Injury

“…Most intriguingly, we recently read with excitement and exaggerated interest, the recent original article by Watanabe et al in the Journal of Clinical Insights, describing a link between inhibition of the renin-angiotensin system and concentric hypertrophy of renal arteries in mice and humans [27]. This report, we must admit, provides the most plausible supporting evidence to our hypotheses and previously expressed opinions on LORFFAB and the concept of microvascular renal artery stenosis [22,27].…”