Renin-Expressing Cells Require β1-Integrin for Survival and for Development and Maintenance of the Renal Vasculature

Mohamed, Tahagod; Watanabe, Hirofumi; Kaur, Rajwinderjit; Belyea, Brian; Walker, Patrick D.; Gómez, R. Ariel; Sequeira-Lόpez, Maria Luisa S.

doi:10.1161/hypertensionaha.120.14959

Cited by 19 publications

(18 citation statements)

References 31 publications

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“…Ablation of the renin cells via long-term conditional deletion of β 1 integrin prevents the arteriolar disease, indicating that renin cells are fully responsible for the arteriolar hypertrophy. In those mice at 4 months of age, the number of renin lineage cells was markedly decreased, consistent with the known role of Itgb1 in the prevention of anoikis and apoptosis in renin lineage cells ( 30 ). Similar results are obtained when renin cells are ablated in mice using diphtheria toxin genetically engineered to be expressed under the control of the renin gene ( 31 ).…”

Section: Discussionsupporting

confidence: 82%

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

Watanabe¹,

Martini²,

Brown³

et al. 2021

JCI Insight

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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.

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Section: Discussionsupporting

confidence: 82%

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

Watanabe¹,

Martini²,

Brown³

et al. 2021

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“…Conditional deletion of Connexin 40 in renin-expressing cells led to mislocalization of JG renin cells and excessive secretion of renin, resulting to malignant hypertension ( Wagner et al, 2007 ). β 1-integrin is required for the development and function of renin cells, and its absence caused a marked decrease in the number of renin cells and vascular alterations ( Mohamed et al, 2020 ).…”

Section: Intrarenal Angiotensin Generation: Location Enzymes Substrat...mentioning

confidence: 99%

Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting

et al. 2022

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E.J.H.). A.N. has received consulting fees, speaking honoraria, or both from Daiichi-Sankyo, Taisho, AstraZeneca, Tanabe-Mitsubishi, and Kowa. A.N. received research funds from Boehringer-Ingelheim, Daiichi-Sankyo, Taisho, and Bayer. A.H.J.D. received research funds from Alnylam Pharmaceuticals. D.B. is coinventor of patents entitled "Active low molecular weight variants of angiotensin converting enzyme 2," "Active low molecular weight variants of angiotensin converting enzyme 2 (ACE2) for the treatment of diseases and conditions of the eye," and "Shorter soluble forms of angiotensin converting enzyme 2 (ACE2) for treating and preventing coronavirus infection." D.B. is founder of Angiotensin Therapeutics Inc. D.B. has received consulting fees from AstraZeneca, Relypsa, and Tricida, all unrelated to this work.1 H.L. and F.G. contributed equally to this work. dx.

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“…This concurs with the study using MIP-Cre to generate Itgb1 -knockout mice, which showed reduced islet vascularization (Win et al, 2020). The involvement of Itgb1 signaling in organ vascularization appears to be a universal requirement: as shown in pituitary endocrine epithelial cells and kidney cells, Itgb1-inactivation leads to vasculature loss (Mohamed et al, 2020; Scully et al, 2016). The expression of Vegfa , an essential growth factor for islet vasculature, is not affected in Itgb1 ΔEndo/ΔEndo islets (Table S2).…”

Section: Discussionmentioning

confidence: 99%

Coordination between ECM and cell-cell adhesion regulates the development of islet aggregation, architecture, and functional maturation

Tixi

Maldonado

Chang

et al. 2022

Preprint

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SUMMARYPancreatic islets are 3-dimensional aggregates consisting of unique cellular composition, cell-to-cell contacts, and interactions with blood vessels. Islet cell aggregation is essential for proper endocrine cell function; however, it remains unclear how developing islets establish aggregation. By combining genetic animal models, imaging tools, and gene expression profiling, we demonstrate that the formation of islet aggregates is regulated by extracellular matrix signaling and cell-cell adhesion. Islet endocrine progenitor cell-specific inactivation of extracellular matrix receptor Integrin β1 disrupted vasculature but promoted cell-cell adhesion and the formation of larger islets, while ablation of cell-cell adhesion molecule α-Catenin promoted vasculature formation yet compromised islet clustering. Simultaneous removal of Integrin β1 and α-Catenin abrogates islet aggregation. These mutants exhibit disruption of the endocrine cell maturation process, demonstrating that establishment of islet aggregates is essential for functional maturation. Our study provides new insights into understanding the fundamental self-organizing mechanism for islet aggregation, architecture, and functional maturation.HIGHLIGHTSIslet vascularization and aggregation are regulated via ECM-Itgb1 signalingECM-Itgb1 signaling negatively controls islet aggregation via regulation of cell-cell adhesion during developmentCell-cell adhesion negatively regulates the interaction of endocrine cell-vasculature in isletsDifferential cell adhesion regulates the establishment of islet architectureEndocrine functional maturation depends on islet aggregation regulated by the coordination of ECM-Itgb1 signaling and cell-cell adhesion

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Renin-Expressing Cells Require β1-Integrin for Survival and for Development and Maintenance of the Renal Vasculature

Cited by 19 publications

References 31 publications

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

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

Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting

Coordination between ECM and cell-cell adhesion regulates the development of islet aggregation, architecture, and functional maturation

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