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 6

Deletion of integrin β1 in renin lineage cells inhibits arteriolar hypertrophy in Ren1c-KO mice.

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Deletion of integrin β1 in renin lineage cells inhibits arteriolar hyper...
(A) Violin plots and ISH for Itgb1 mRNA in Reninnull cells. Scale bars: 50 μm. (B) Immunofluorescence staining for α-SMA and integrin β1 in kidneys from Ren1c-KO control and Ren1c-KO with Itgb1-cKO mice. Arrows indicate the α-SMA–positive cells at the JG area. Integrin β1 was not observed at the JG area of the Ren1c-KO Itgb1-cKO mice. Scale bars: 20 μm. (C and D) Arteriolar hypertrophy was prevented in Ren1c-KO Itgb1-cKO mice. Immunohistochemistry for α-SMA showed decreased thickness of the walls of afferent arterioles in Ren1c-KO Itgb1-cKO mice compared with Ren1c-KO control (C). Scale bars: 50 μm. The mean wall thickness of afferent arterioles at the JG area was significantly smaller in Ren1c-KO Itgb1-cKO mice (n = 6, Student’s t test) (D). Relative frequency distribution histograms show that the distribution curve corresponding to the Ren1c-KO Itgb1-cKO mice is displaced to the left of the control mice (D). (E) ISH for Akr1b7 mRNA in kidneys from Ren1c-KO Itgb1-c-KO and Ren1c-KO control mice. The number of Akr1b7 mRNA-positive cells in Ren1c-KO Itgb1-cKO mice is much smaller than in Ren1c-KO controls. Arrows indicate afferent arterioles. Scale bars: 50 μm. (F) GFP showed in the walls of hypertrophic afferent arterioles in the Ren1c-KO control (Ren1c-KO–/– Ren1cCre/+ Itgb1fl/+ R26mTmG) but was absent in the arterioles of Ren1c-KO Itgb1-cKO kidneys (Ren1c-KO–/– Ren1cCre/+ Itgb1fl/fl R26mTmG) while persisting in some tubules. Scale bars: 50 μm. (G) PAS staining and Masson’s trichrome staining in kidneys from Ren1c-KO and Ren1c-KO Itgb1-cKO mice showed fibrosis in both groups. Scale bars: 50 μm. All data are reported as means ± standard deviation. Black triangles represent male samples and purple dots female samples. ****P < 0.0001. Itgb1-cKO, deletion of the Itgb1 gene in cells of the renin lineage; JG, juxtaglomerular; PAS, periodic acid–Schiff; Ren1c-KO, Ren1c gene knockout.