Inhibition of the renin-angiotensin system causes concentric hypertrophy of renal arterioles in mice and humans
Hirofumi Watanabe, Alexandre G. Martini, Robin Isadora Brown, Xiuyin Liang, Silvia Medrano, Shin Goto, Ichiei Narita, Lois J. Arend, Maria Luisa S. Sequeira-Lopez, R. Ariel Gomez
Hirofumi Watanabe, Alexandre G. Martini, Robin Isadora Brown, Xiuyin Liang, Silvia Medrano, Shin Goto, Ichiei Narita, Lois J. Arend, Maria Luisa S. Sequeira-Lopez, R. Ariel Gomez
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Research Article Nephrology Vascular biology

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 β1 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.

Authors

Hirofumi Watanabe, Alexandre G. Martini, Robin Isadora Brown, Xiuyin Liang, Silvia Medrano, Shin Goto, Ichiei Narita, Lois J. Arend, Maria Luisa S. Sequeira-Lopez, R. Ariel Gomez

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Figure 1

Reninnull cells have different transcriptomic profiles.

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Reninnull cells have different transcriptomic profiles. (A) Pathologica...
(A) Pathological findings of Ren1c-KO mice. Immunohistochemistry for α-SMA showed hypertrophic arterioles in Ren1c-KO mouse kidneys. Scale bars: 20 μm. Kidney sections from Ren1c-KO Ren1c-Cre Confetti mice showed multiple colors in the hypertrophic arterioles, suggesting the multiclonality of Reninnull cells. Scale bars: 20 μm. Left: WT mice showed normal architecture of periglomerular arterioles with a single layer of smooth muscle cells (SMCs). Right: Ren1c-KO mice showed concentric hypertrophy of arteriolar smooth muscle. Scale bars: 10 μm. (B) Schematic of scRNA-Seq of WT renin cells and Reninnull cells. Ren1c-YFP mice have a transgene consisting of the YFP genes driven by the Ren1c gene regulatory region. YFP-positive kidney cells from Ren1c+/+ Ren1c-YFP mice and Ren1c–/– Ren1c-YFP mice were isolated by FACS. Single cells were captured with the Fluidigm C1 System, and scRNA-Seq was performed. Scale bars: 50 μm. (C) The UMAP with all the cells after normalization. (D) Volcano plot showing the differentially expressed genes between WT renin cells and Reninnull cells. (E) Heatmap analysis with differentially expressed genes showed a clear separation of WT renin cells and Reninnull cells. (F) The 10 most enriched categories identified by GO analysis on genes higher in WT renin cells (red) and genes higher in Reninnull cells (blue). (G) Venn diagram showing differentially expressed genes. α-SMA, α–smooth muscle actin; EM, electron microscopy; FACS, fluorescence-activated cell sorting; GO, Gene Ontology; Ren1c-KO, Ren1c gene knockout; scRNA-Seq, single-cell RNA sequencing; UMAP, uniform manifold approximation and projection; WT, wild-type.