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Low Dose Chronic Angiotensin II Induces Selective Senescence of Kidney Endothelial Cells.

ABSTRACT: Angiotensin II can cause oxidative stress and increased blood pressure that result in long term cardiovascular pathologies. Here we evaluated the contribution of cellular senescence to the effect of chronic exposure to low dose angiotensin II in a model that mimics long term tissue damage. We utilized the INK-ATTAC (p16^Ink4a-Apoptosis Through Targeted Activation of Caspase 8) transgenic mouse model that allows for conditional elimination of p16^Ink4a -dependent senescent cells by administration of AP20187. Angiotensin II treatment for 3 weeks induced ATTAC transgene expression in kidneys but not in lung, spleen and brain tissues. In the kidneys increased expression of ATM, p15 and p21 matched with angiotensin II induction of senescence-associated secretory phenotype genes MMP3, FGF2, IGFBP2, and tPA. Senescent cells in the kidneys were identified as endothelial cells by detection of GFP expressed from the ATTAC transgene and increased expression of angiopoietin 2 and von Willebrand Factor, indicative of endothelial cell damage. Furthermore, angiotensin II induced expression of the inflammation-related glycoprotein versican and immune cell recruitment to the kidneys. AP20187-mediated elimination of p16-dependent senescent cells prevented physiologic, cellular and molecular responses to angiotensin II and provides mechanistic evidence of cellular senescence as a driver of angiotensin II effects.

SUBMITTER: Khan I

PROVIDER: S-EPMC8696590 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Low dose chronic angiotensin II induces selective senescence of kidney endothelial cells

Project description:Here we evaluated the contribution of cellular senescence to the effect of chronic exposure to low dose angiotensin II in a mouse model that mimics the initiation of hypertension. We utilized the INK-ATTAC (p16ink4a - Apoptosis Through Targeted Activation of Caspase 8) mouse model that allows for conditional elimination of p16ink4a -dependent senescent cells by administration of AP20187. INK-ATTAC mice received continuous low doses of angiotensin II over 3 weeks and AP20187 vs vehicle. In the kidneys increased expression of ATM, p15 and p21 matched with angiotensin II induction of senescence-associated secretory phenotype genes MMP3, FGF2, IGFBP2, and tPA. AP20187-mediated elimination of p16-dependent senescent cells prevented physiologic, cellular and molecular responses to angiotensin II. We conclude that angiotensin II induces a relatively selective senescence transformation of renal endothelial cells that could provide a novel therapeutic target for senolytic drugs as alternative treatment options for hypertension and resulting tissue damage.

2022-01-10 | GSE179195 | GEO

Low dose chronic angiotensin II induces selective senescence of kidney endothelial cells

Project description:Low dose chronic angiotensin II induces selective senescence of kidney endothelial cells

| PRJNA742686 | ENA

Thrombin Induces Angiotensin II-Mediated Senescence in Atrial Endothelial Cells: Impact on Pro-Remodeling Patterns.

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| S-EPMC6833093 | biostudies-literature

Angiotensin II induces endothelial dysfunction and vascular remodeling by downregulating TRPV4 channels.

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MicroRNA let-7g inhibits angiotensin II-induced endothelial senescence via the LOX-1-independent mechanism.

Project description:Endothelial senescence leads to cell dysfunction, which in turn eventually results in cardiovascular disease. Identifying factors that regulate endothelial senescence may provide insight into the pathogenesis of aging. Insulin-like growth factor (IGF) signaling has a significant role in the physiology of endothelial cells (ECs). Overactivation of IGF signaling has been implicated in promoting the aging process. Lectin?like oxidized low?density lipoprotein (oxLDL) receptor?1 (LOX?1) is a scavenger receptor that mediates the internalization of oxLDL into cells. Previous studies by our group have indicated that microRNA let?7g exerts an anti?aging effect on ECs and also suppresses LOX-1 expression. Since LOX?1 also induces the aging process, the present study we explored whether let?7g still exerts an anti?aging effect on ECs when LOX?1 is suppressed. Angiotensin II (Ang II) was used to induce senescence in ECs. It was revealed that Ang II significantly increased the expression of aging markers, including ??galactosidase, LOX?1, IGF1 and its receptor IGF1R. On the contrary, Ang II decreased the expression of the anti?aging gene sirtuin 1 (SIRT1). When LOX?1 was knocked down by small interfering RNA, let?7g still dose?dependently decreased the expression of ??galactosidase (??gal), LOX?1, IGF1 and IGF1R, and SIRT1 was still upregulated. Using senescence?associated ??gal staining, it was confirmed that let?7g exerts a LOX?1?independent anti?aging effect on ECs. In conclusion, the present study demonstrated that let?7g has an anti?aging effect regardless of the presence or absence of LOX-1.

| S-EPMC5810198 | biostudies-literature

Involvement of Senescence and Mitochondrial Fission in Endothelial Cell Pro-Inflammatory Phenotype Induced by Angiotensin II.

Project description:Angiotensin II (AngII) has a crucial role in cardiovascular pathologies, including endothelial inflammation and premature vascular aging. However, the precise molecular mechanism underlying aging-related endothelial inflammation induced by AngII remains elusive. Here, we have tested a hypothesis in cultured rat aortic endothelial cells (ECs) that the removal of AngII-induced senescent cells, preservation of proteostasis, or inhibition of mitochondrial fission attenuates the pro-inflammatory EC phenotype. AngII stimulation in ECs resulted in cellular senescence assessed by senescence-associated β galactosidase activity. The number of β galactosidase-positive ECs induced by AngII was attenuated by treatment with a senolytic drug ABT737 or the chemical chaperone 4-phenylbutyrate. Monocyte adhesion assay revealed that the pro-inflammatory phenotype in ECs induced by AngII was alleviated by these treatments. AngII stimulation also increased mitochondrial fission in ECs, which was mitigated by mitochondrial division inhibitor-1. Pretreatment with mitochondrial division inhibitor-1 attenuated AngII-induced senescence and monocyte adhesion in ECs. These findings suggest that mitochondrial fission and endoplasmic reticulum stress have causative roles in endothelial senescence-associated inflammatory phenotype induced by AngII exposure, thus providing potential therapeutic targets in age-related cardiovascular diseases.

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An angiotensin II receptor blocker-calcium channel blocker combination prevents cardiovascular events in elderly high-risk hypertensive patients with chronic kidney disease better than high-dose angiotensin II receptor blockade alone.

Project description:The OSCAR study was a multicenter, prospective randomized open-label blinded end-point study of 1164 Japanese elderly hypertensive patients comparing the efficacy of angiotensin II receptor blocker (ARB) uptitration to an ARB plus calcium channel blocker (CCB) combination. In this prospective study, we performed prespecified subgroup analysis according to baseline estimated glomerular filtration rate (eGFR) with chronic kidney disease (CKD) defined as an eGFR <60 ml/min per 1.73 m(2). Blood pressure was lower in the combined therapy than in the high-dose ARB cohort in both groups with and without CKD. In patients with CKD, significantly more primary events (a composite of cardiovascular events and noncardiovascular death) occurred in the high-dose ARB group than in the combination group (30 vs. 16, respectively, hazard ratio 2.25). Significantly more cerebrovascular and more heart failure events occurred in the high-dose ARB group than in the combination group. In patients without CKD, however, the incidence of primary events was similar between the two treatments. The treatment-by-subgroup interaction was significant. Allocation to the high-dose ARB was a significant independent prognostic factor for primary events in patients with CKD. Thus, the ARB plus CCB combination conferred greater benefit in prevention of cardiovascular events in patients with CKD compared with high-dose ARB alone. Our findings provide new insight into the antihypertensive strategy for elderly hypertensive patients with CKD.

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Association between angiotensin II receptor type 1 A1166C polymorphism and chronic kidney disease.

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Angiotensin II induces kidney inflammatory injury and fibrosis through binding to myeloid differentiation protein-2 (MD2).

Project description:Growing evidence indicates that angiotensin II (Ang II), a potent biologically active product of RAS, is a key regulator of renal inflammation and fibrosis. In this study, we tested the hypothesis that Ang II induces renal inflammatory injury and fibrosis through interaction with myeloid differentiation protein-2 (MD2), the accessory protein of toll-like receptor 4 (TLR4) of the immune system. Results indicated that in MD2-/- mice, the Ang II-induced renal fibrosis, inflammation and kidney dysfunction were significantly reduced compared to control Ang II-infused wild-type mice. Similarly, in the presence of small molecule MD2 specific inhibitor L6H21 or siRNA-MD2, the Ang II-induced increases of pro-fibrotic and pro-inflammatory molecules were prevented in tubular NRK-52E cells. MD2 blockade also inhibited activation of NF-κB and ERK. Moreover, MD2 blockade prevented the Ang II-stimulated formation of the MD2/TLR4/MyD88 signaling complex, as well as the increased surface binding of Ang II in NRK-52E cells. In addition, Ang II directly bound recombinant MD2 protein, rather than TLR4 protein. We conclude that MD2 is a significant contributor in the Ang II-induced kidney inflammatory injury in chronic renal diseases. Furthermore, MD2 inhibition could be a new and important therapeutic strategy for preventing progression of chronic renal diseases.

| S-EPMC5359637 | biostudies-literature

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