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

He, Xin; Jiang, Hongli; Gao, Fei; Liang, Shanshan; Wang, Meng; Chen, Lei

doi:10.1002/jemt.23369

Cited by 41 publications

(33 citation statements)

References 39 publications

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“…Furthermore, vascular effects of IS might also contribute to progression of CKD. IS promotes vascular calcification [ 18 ] and inflammation [ 19 ] in vitro and in animal models of CKD [ 20 ]. Moreover, serum IS levels are associated with the surrogate markers of cardiovascular disease (intima media thickness and pulse walve velocity) in children [ 5 ] and with diminished endothelial function in adults with CKD [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Serum indoxyl sulfate concentrations associate with progression of chronic kidney disease in children

et al. 2020

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The uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (pCS) accumulate in patients with chronic kidney disease (CKD) as a consequence of altered gut microbiota metabolism and a decline in renal excretion. Despite of solid experimental evidence for nephrotoxic effects, the impact of uremic toxins on the progression of CKD has not been investigated in representative patient cohorts. In this analysis, IS and pCS serum concentrations were measured in 604 pediatric participants (mean eGFR of 27 ± 11 ml/min/1.73m2) at enrolment into the prospective Cardiovascular Comorbidity in Children with CKD study. Associations with progression of CKD were analyzed by Kaplan-Meier analyses and Cox proportional hazard models. During a median follow up time of 2.2 years (IQR 4.3–0.8 years), the composite renal survival endpoint, defined as 50% loss of eGFR, or eGFR <10ml/min/1.73m2 or start of renal replacement therapy, was reached by 360 patients (60%). Median survival time was shorter in patients with IS and pCS levels in the highest versus lowest quartile for both IS (1.5 years, 95%CI [1.1,2.0] versus 6.0 years, 95%CI [5.0,8.4]) and pCS (1.8 years, 95%CI [1.5,2.8] versus 4.4 years, 95%CI [3.4,6.0]). Multivariable Cox regression disclosed a significant association of IS, but not pCS, with renal survival, which was independent of other risk factors including baseline eGFR, proteinuria and blood pressure. In this exploratory analysis we provide the first data showing a significant association of IS, but not pCS serum concentrations with the progression of CKD in children, independent of other known risk factors. In the absence of comorbidities, which interfere with serum levels of uremic toxins, such as diabetes, obesity and metabolic syndrome, these results highlight the important role of uremic toxins and accentuate the unmet need of effective elimination strategies to lower the uremic toxin burden and abate progression of CKD.

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Section: Discussionmentioning

confidence: 99%

Serum indoxyl sulfate concentrations associate with progression of chronic kidney disease in children

et al. 2020

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“…The enzyme ALP is able to hydrolyze PPi into phosphate ions [69]. An increase in ALP activity along with increased calcification in VSMC or MSC was shown for cytidine, threitol and urea [41] (Table 1); VCAM-1 [48], FGF2, PTH, TNF-α, and IL-1β [41] (Table 2), as well as for indoxyl sulphate [54] (Table 3).…”

Section: Alkaline Phosphatasementioning

confidence: 96%

“…(Table 3) In human VSMC, indoxyl sulphate increased calcium content when added to pro-calcifying incubation medium [30] and induced calcification as shown by alizarin red staining [30,[51][52][53][54]. In parallel, it reduced the expression of α-SMA [30,51,54] and SM22-α [30], but upregulated CBFA1/RUNX2 [30,[51][52][53][54], osteopontin [30,[51][52][53], ALP, and BMP2 [30,51]. Rat aortic rings incubated in high phosphate media in the presence of indoxyl sulphate had increased calcium content and showed enhanced calcification in alizarin red staining [30].…”

Section: Middle Molecular Weight Substances Increased In Blood In Ckmentioning

confidence: 99%

“…Indoxyl sulphate (Table 3): Parallel to inducing vascular calcification, indoxyl sulphate administration to human VSMC [30,[51][52][53][54] or rats with hypertension [57] or 5/6 nephrectomy [51] increased the expression of CBFA1/RUNX2, ALP, BMP2 and osteopontin, while a reduction in α-SMA, SM22-α and/or SMTN expression could be observed. Recent in vitro data showed that indoxyl sulphate-induced osteogenic transdifferentiation and calcification of VSMC is mediated by the NF-κB and PI3K/AKT pathways [54].…”

Section: Vsmc Osteogenic Transdifferentiationmentioning

confidence: 99%

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Uremic Toxins Affecting Cardiovascular Calcification: A Systematic Review

Holmar

Puente-Secades

Floege

et al. 2020

Cells

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Cardiovascular calcification is highly prevalent and associated with increased morbidity in chronic kidney disease (CKD). This review examines the impact of uremic toxins, which accumulate in CKD due to a failing kidney function, on cardiovascular calcification. A systematic literature search identified 41 uremic toxins that have been studied in relation to cardiovascular calcification. For 29 substances, a potentially causal role in cardiovascular calcification was addressed in in vitro or animal studies. A calcification-inducing effect was revealed for 16 substances, whereas for three uremic toxins, namely the guanidino compounds asymmetric and symmetric dimethylarginine, as well as guanidinosuccinic acid, a calcification inhibitory effect was identified in vitro. At a mechanistic level, effects of uremic toxins on calcification could be linked to the induction of inflammation or oxidative stress, smooth muscle cell osteogenic transdifferentiation and/or apoptosis, or alkaline phosphatase activity. For all middle molecular weight and protein-bound uremic toxins that were found to affect cardiovascular calcification, an increasing effect on calcification was revealed, supporting the need to focus on an increased removal efficiency of these uremic toxin classes in dialysis. In conclusion, of all uremic toxins studied with respect to calcification regulatory effects to date, more uremic toxins promote rather than reduce cardiovascular calcification processes. Additionally, it highlights that only a relatively small part of uremic toxins has been screened for effects on calcification, supporting further investigation of uremic toxins, as well as of associated post-translational modifications, on cardiovascular calcification processes.

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“…Moreover, TNF-α also enhanced osteogenic differentiation of both human bone marrow-derived mesenchymal stem cells and human dental pulp stem cells through activation of NF-κB signaling pathway [38,39]. Furthermore, NF-κB signaling stimulated by various stimuli such as high glucose, high phosphate, and oxidative stress as well as proinflammatory cytokines has also been involved in osteogenic differentiation of VSMCs [40][41][42][43][44]. Therefore, NF-κB signaling play a pivotal role in osteogenic differentiation of not only mesenchymal stem cells, but also VSMCs.…”

Section: Inflammation and Vascular Calcificationmentioning

confidence: 99%

The Inhibitory Roles of Vitamin K in Progression of Vascular Calcification

et al. 2020

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Vitamin K is a fat-soluble vitamin that is indispensable for the activation of vitamin K-dependent proteins (VKDPs) and may be implicated in cardiovascular disease (CVD). Vascular calcification is intimately associated with CV events and mortality and is a chronic inflammatory process in which activated macrophages promote osteoblastic differentiation of vascular smooth muscle cells (VSMCs) through the production of proinflammatory cytokines such as IL-1β, IL-6, TNF-α, and oncostatin M (OSM) in both intimal and medial layers of arterial walls. This process may be mainly mediated through NF-κB signaling pathway. Vitamin K has been demonstrated to exert anti-inflammatory effects through antagonizing NF-κB signaling in both in vitro and in vivo studies, suggesting that vitamin K may prevent vascular calcification via anti-inflammatory mechanisms. Matrix Gla protein (MGP) is a major inhibitor of soft tissue calcification and contributes to preventing both intimal and medial vascular calcification. Vitamin K may also inhibit progression of vascular calcification by enhancing the activity of MGP through facilitating its γ-carboxylation. In support of this hypothesis, the procalcific effects of warfarin, an antagonist of vitamin K, on arterial calcification have been demonstrated in several clinical studies. Among the inactive MGP forms, dephospho-uncarboxylated MGP (dp-ucMGP) may be regarded as the most useful biomarker of not only vitamin K deficiency, but also vascular calcification and CVD. There have been several studies showing the association of circulating levels of dp-ucMGP with vitamin K intake, vascular calcification, mortality, and CVD. However, additional larger prospective studies including randomized controlled trials are necessary to confirm the beneficial effects of vitamin K supplementation on CV health.

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

Cited by 41 publications

References 39 publications

Serum indoxyl sulfate concentrations associate with progression of chronic kidney disease in children

Serum indoxyl sulfate concentrations associate with progression of chronic kidney disease in children

Uremic Toxins Affecting Cardiovascular Calcification: A Systematic Review

The Inhibitory Roles of Vitamin K in Progression of Vascular Calcification

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