Indoxyl Sulfate-Induced Activation of (Pro)renin Receptor Promotes Cell Proliferation and Tissue Factor Expression in Vascular Smooth Muscle Cells

Yisireyili, Maimaiti; Saito, Shinichi; Abudureyimu, Shaniya; Adelibieke, Yelixiati; Ng, Hwee-Yeong; Nishijima, Fuyuhiko; Takeshita, Kyosuke; Murohara, Toyoaki; Niwa, Toshimitsu

doi:10.1371/journal.pone.0109268

Cited by 50 publications

(47 citation statements)

References 45 publications

(78 reference statements)

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“…All these results demonstrate that IS has pro-hypertrophic effect on cardiomyocytes. Besides, we also found that IS could suppress the proliferation and increase cytotoxicity in NRCMs, which is consistent with previous reports that IS has toxic effects on other kinds of cells (Wang et al, 2014;Yisireyili et al, 2014). Based on the results of DCFH-DA staining, we further found that IS treatment increased ROS generation in NRCMs in a dose-dependent manner.…”

Section: Discussionsupporting

confidence: 91%

Indoxyl sulfate induces oxidative stress and hypertrophy in cardiomyocytes by inhibiting the AMPK/UCP2 signaling pathway

Yang

Nie

et al. 2015

Toxicology Letters

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Section: Discussionsupporting

confidence: 91%

Indoxyl sulfate induces oxidative stress and hypertrophy in cardiomyocytes by inhibiting the AMPK/UCP2 signaling pathway

Yang

Nie

et al. 2015

Toxicology Letters

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“…20 Our data indicate a direct interaction ( Figure 3B) and regulation of TF through AHR; however, an indirect regulation is also likely. 27 All of these data support multiple mechanisms of AHR-mediated TF regulation in different cell types underscoring its critical role in TF biology.…”

Section: Discussionmentioning

confidence: 71%

The Aryl Hydrocarbon Receptor is a Critical Regulator of Tissue Factor Stability and an Antithrombotic Target in Uremia

Shivanna

Kolandaivelu

Shashar

et al. 2016

Journal of the American Society of Nephrology

146

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Patients with CKD suffer high rates of thrombosis, particularly after endovascular interventions, yet few options are available to improve management and reduce thrombotic risk. We recently demonstrated that indoxyl sulfate (IS) is a potent CKD-specific prothrombotic metabolite that induces tissue factor (TF) in vascular smooth muscle cells (vSMCs), although the precise mechanism and treatment implications remain unclear. Because IS is an agonist of the aryl hydrocarbon receptor (AHR), we first examined the relationship between IS levels and AHR-inducing activity in sera of patients with ESRD. IS levels correlated significantly with both vSMC AHR activity and TF activity. Mechanistically, we demonstrated that IS activates the AHR pathway in primary human aortic vSMCs, and further, that AHR interacts directly with and stabilizes functional TF. Antagonists directly targeting AHR enhanced TF ubiquitination and degradation and suppressed thrombosis in a postinterventional model of CKD and endovascular injury. Furthermore, AHR antagonists inhibited TF in a manner dependent on circulating IS levels. In conclusion, we demonstrated that IS regulates TF stability through AHR signaling and uncovered AHR as an antithrombotic target and AHR antagonists as a novel class of antithrombotics. Together, IS and AHR have potential as uremia-specific biomarkers and targets that may be leveraged as a promising theranostic platform to better manage the elevated thrombosis rates in patients with CKD.

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“…It provided a new cell model to investigate the function of mimecan in VSMCs. The HASMCs used in the present study were purchased from Cascade Biologics and have been used in a number of previous studies to investigate VSMCs (15,16).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of mimecan in human aortic smooth muscle cells inhibits cell proliferation and enhances apoptosis and migration

Zhang

Wang

Liu

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. The pathogenesis of atherosclerosis is multi factorial. The proliferation and migration of vascular smooth muscle cells (VSMCs) are significant in the genesis and development of atherosclerosis plaques, and the degradation of VSMCs plays a crucial role in the process. Mimecan is a member of the Keratan sulfate family of proteoglycans, which are leucine-rich proteoglycans. It has been demonstrated that mimecan is associated with arteriogenesis and atherosclerosis. In the present study, the effect of mimecan on the characteristics of cultured human aortic smooth muscle cells (HASMCs) was investigated. In vitro, human mimecan was stably overexpressed in HASMCs using a lentiviral system. It was observed that the proliferation rate of HASMCs transduced with mimecan was lower compared with that of control cells; overexpression of mimecan induced HASMC apoptosis. To determine the effect of mimecan on HASMC migration, a Transwell cell culture chamber and sterile cloning cylinder assays were used, and it was noted that mimecan enhanced the migration of HASMCs horizontally and vertically. These data indicated that mimecan may be involved in the pathogenesis of atherosclerosis by regulating the proliferation, apoptosis and migration of VSMCs.

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Indoxyl Sulfate-Induced Activation of (Pro)renin Receptor Promotes Cell Proliferation and Tissue Factor Expression in Vascular Smooth Muscle Cells

Cited by 50 publications

References 45 publications

Indoxyl sulfate induces oxidative stress and hypertrophy in cardiomyocytes by inhibiting the AMPK/UCP2 signaling pathway

Indoxyl sulfate induces oxidative stress and hypertrophy in cardiomyocytes by inhibiting the AMPK/UCP2 signaling pathway

The Aryl Hydrocarbon Receptor is a Critical Regulator of Tissue Factor Stability and an Antithrombotic Target in Uremia

Overexpression of mimecan in human aortic smooth muscle cells inhibits cell proliferation and enhances apoptosis and migration

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