Indoxyl sulfate accelerates vascular smooth muscle cell calcification via microRNA-29b dependent regulation of Wnt/β-catenin signaling

Zhang, Han; Chen, Jing; Shen, Ziyan; Gu, Yan; Xu, L.Y.; Hu, Jiayue; Zhang, Xiaoyan; Ding, Xiaoqiang

doi:10.1016/j.toxlet.2017.11.033

Cited by 67 publications

(53 citation statements)

References 36 publications

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“…Our study indicated that Wnt pathway was involved in CKD VC, which is consistent with previous studies . Addition of Wnt pathway inhibitor secreted frizzeled‐related protein 5 could inhibit high phosphate‐induced calcification of VSMCs .…”

Section: Disccusionsupporting

confidence: 92%

“…Our study indicated that Wnt pathway was involved in CKD VC, which is consistent with previous studies. 6,[20][21][22][23][24][25][26] Addition of Wnt pathway inhibitor secreted frizzeled-related protein 5 could inhibit high phosphate-induced calcification of VSMCs. 23 Dysregulation of klotho, which is an intrinsic inhibitor of Wnt-signaling, was also shown to be associated with CKD VC.…”

Section: Disccusionmentioning

confidence: 99%

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Vascular calcification is associated with Wnt‐signaling pathway and blood pressure variability in chronic kidney disease rats

Liao

Wang

et al. 2019

Nephrology

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Aim Vascular calcification (VC) is a common complication in chronic kidney disease (CKD) and has been shown to be associated with increased cardiovascular events and mortality. This study was to explore the role of Wnt‐signaling pathway in CKD VC, and the association between VC and blood pressure variability (BPV) which is a risk factor of cardiovascular events. Methods Adult male Sprague‐Dawley rats were divided into adenine‐induced CKD group (n = 5), 5/6 nephrectomy CKD group (n = 5), sham group (n = 5) and control group (n = 5). Low‐calcium‐high‐phosphate diets were introduced to induce vascular calcification. Both daytime (hour‐to‐hour during the day) and mid‐term (day‐to‐day for 9 days) blood pressure (BP) were collected and analyzed for BPV metrics. At sacrifice, kidney, heart and aorta samples were taken for histological analyses. Calcium deposition in aorta was identified with Alizarin Red stain and graded. Immunohistochemistry stain and western blot were performed for Wnt3a, Wnt5a, β‐catenin, sclerostin, osteopontin, and α‐SMA. Results Compared with control rats, CKD rats suffered from markedly severer VC (Grade 2.6 ± 0.2 and 1.8 ± 0.8 vs 0.0 ± 0.0 and 0.2 ± 0.4, P = .0010). VC was positively correlated with vascular Wnt3a and β‐catenin expression (P = .0032 and .0000), but not significantly associated with Wnta5a or sclerostin. Besides, CKD rats showed increased BPV (P < .001), which was also positively correlated with VC. Conclusion We confirmed that CKD rats had enhanced Wnt‐signaling in vascular tissue and severer aorta calcification together with increased BPV. Wnt pathway may be a potential target in future VC and BPV management in CKD.

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Section: Disccusionsupporting

confidence: 92%

Section: Disccusionmentioning

confidence: 99%

Vascular calcification is associated with Wnt‐signaling pathway and blood pressure variability in chronic kidney disease rats

Liao

Wang

et al. 2019

Nephrology

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“…IS, one of the most important uremic toxins that have profound effects on endothelial dysfunction and VC (Chen et al, ; Shang et al, ). It has been reported that IS stimulation promotes phenotypic switch of VSMCs from a contractile phenotype to an osteogenic phenotype (Muteliefu, Enomoto, Jiang, Takahashi, & Niwa, ; Zhang et al, ). Although IS has been confirmed as a major cause of VC in CKD patients, the underlying mechanism is not understood completely.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms by which IS cause the VC are very complicated. Previous studies from in vivo and in vitro have demonstrated that IS promotes the osteogenic transdifferentiation of VSMC ensuing VC via various signaling pathways, including Wnt/β‐catenin signaling, JNK/Pit‐1 pathway, and epigenetic regulation (Chen et al, ; Wu, Xue, Wang, Diao, & Liu, ; Zhang et al, ). However, the specific mechanism by which IS modulates the osteogenic transdifferentiation of VSMC has not been fully uncovered.…”

Section: Introductionmentioning

confidence: 99%

Indoxyl sulfate‐induced calcification of vascular smooth muscle cells via the PI3K/Akt/NF‐κB signaling pathway

Jiang

Gao

et al. 2019

Microscopy Res & Technique

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Vascular calcification (VC) is highly prevalent in patients with chronic kidney disease (CKD) and contributes to their high rate of cardiovascular mortality. Indoxyl sulfate (IS) is a representative protein-bound uremic toxin in CKD patients, which has been recognized as a major risk factor for VC. Recent studies have demonstrated that nuclear factor-kappa B (NK-κB) is highly activated in the chronic inflammation conditions of CKD patients and participated in the pathogenesis of VC. However, whether NK-κB is involved in the progression of IS-induced VC remains without elucidation.Here, we showed that NK-κB activity was increased in the IS-induced calcification of human aortic smooth muscle cells (HASMCs). Blocking the NK-κB with a selective inhibitor (Bay-11-7082) significantly relieved the osteogenic transdifferentiation of HASMCs, characterized by the downregulation of early osteogenic-specific marker, core-binding factor alpha subunit 1 (Cbfα1), and upregulation of smooth muscle α-actin (α-SMA), a specific vascular smooth muscle cell marker. Besides, IS stimulated the activation of PI3K/Akt signaling. Furthermore, LY294002, a specific inhibitor of PI3K/Akt pathway, attenuated the activation of NK-κB and osteogenic differentiation of HASMCs. Together, these results suggest that PI3K/Akt/NK-κB signaling plays an important role in the pathogenesis of osteogenic transdifferentiation induced by IS. K E Y W O R D S chronic kidney disease, indoxyl sulfate, nuclear factor-kappa B, osteogenic differentiation

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“…It has been shown that miRNAs in humans are involved in, among other things, the regulation of processes such as hematopoietic stem cell differentiation, neurogenesis, embryogenesis, angiogenesis, insulin secretion, differentiation of mononuclear cells and the formation and activity of immune system cells [65][66][67][68]. Moreover, their significance in such conditions as inflammation, cancers, autoimmune diseases and cardiovascular diseases has been confirmed [64,[69][70][71][72][73][74][75][76][77][78][79][80][81][82]. The usefulness of miRNAs as biomarkers in cardiovascular diseases results from their participation in pathophysiological processes related to cardiovascular diseases as well as their stability in blood and urine [83].…”

Section: The Participation Of Micro-rna In Inflammation In Hfmentioning

confidence: 99%

Various aspects of inflammation in heart failure

et al. 2019

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Despite significant advances in the prevention and treatment of heart failure (HF), the prognosis in patients who have been hospitalised on at least one occasion due to exacerbation of HF is still poor. Therefore, a better understanding of the underlying pathophysiological mechanisms of HF is crucial in order to achieve better results in the treatment of this clinical syndrome. One of the areas that, for years, has aroused the interest of researchers is the activation of the immune system and the elevated levels of biomarkers of inflammation in patients with both ischaemic and non-ischaemic HF. Additionally, it is intriguing that the level of circulating pro-inflammatory biomarkers correlates with the severity of the disease and prognosis in this group of patients. Unfortunately, clinical trials aimed at assessing interventions to modulate the inflammatory response in HF have been disappointing, and the modulation of the inflammatory response has had either no effect or even a negative effect on the HF prognosis. The article presents a summary of current knowledge on the role of immune system activation and inflammation in the pathogenesis of HF. Understanding the immunological mechanisms pathogenetically associated with left ventricular remodelling and progression of HF may open up new therapeutic possibilities for HF.

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Indoxyl sulfate accelerates vascular smooth muscle cell calcification via microRNA-29b dependent regulation of Wnt/β-catenin signaling

Cited by 67 publications

References 36 publications

Vascular calcification is associated with Wnt‐signaling pathway and blood pressure variability in chronic kidney disease rats

Vascular calcification is associated with Wnt‐signaling pathway and blood pressure variability in chronic kidney disease rats

Indoxyl sulfate‐induced calcification of vascular smooth muscle cells via the PI3K/Akt/NF‐κB signaling pathway

Various aspects of inflammation in heart failure

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