Erythropoietin attenuates vascular calcification by inhibiting endoplasmic reticulum stress in rats with chronic kidney disease

Chang, Jiao; Sun, Ning; Liu, Yue; Wei, Ming; Zhao, Yan; Gan, Lu; Zhu, Jun; Su, Xingli

doi:10.1016/j.peptides.2019.170181

Cited by 19 publications

(8 citation statements)

References 41 publications

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“…Thus, impaired mineralization in OI #3 with a glycine substitution mutation might be caused by the deterioration of mineralization activity and not from the impairment of osteoblast differentiation. In contrast to our data of remarkable improvement in mineralization in OI #3-induced osteoblasts, 4-PBA was reported to have the effect of preventing calcification of vascular smooth muscle cells (39) and valvular interstitial cells (40) by inhibiting ER stress. The difference in cell types between our study and previous study may explain the calcification-promoting effect of 4-PBA in induced osteoblasts in our data.…”

Section: Discussioncontrasting

confidence: 99%

4-Phenylbutyric acid enhances the mineralization of osteogenesis imperfecta iPSC-derived osteoblasts

Takeyari

Kubota

Ohata

et al. 2021

Journal of Biological Chemistry

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Osteogenesis imperfecta (OI) is a heritable brittle bone disease mainly caused by mutations in the two type I collagen genes. Collagen synthesis is a complex process including trimer formation, glycosylation, secretion, extracellular matrix (ECM) formation and mineralization. Using OI patient-derived fibroblasts and induced pluripotent stem cells (iPSCs), we investigated the effect of 4-phenylbutyric acid (4-PBA) on collagen synthesis to test its potential as a new treatment for OI. Endoplasmic reticulum (ER) retention of type I collagen was observed by immunofluorescence staining in OI patient-derived fibroblasts with glycine substitution and exon skipping mutations. Liquid chromatography-mass spectrometry analysis revealed excessive glycosylation of secreted type I collagen at the specific sites in OI cells. The misfolding of the type I collagen triple helix in the ECM was demonstrated by the incorporation of heat-dissociated collagen hybridizing peptide in OI cells. Type I collagen was produced excessively by OI fibroblasts with a glycine mutation, but this excessive production was normalized when OI fibroblasts were cultured on control fibroblast-derived ECM. We also found that mineralization was impaired in osteoblasts differentiated from OI iPSCs. In summary, treatment with 4-PBA normalizes the excessive production of type I collagen, reduces ER retention, partially improves misfolding of the type I collagen helix in ECM and improves osteoblast mineralization. Thus, 4-PBA may improve not only ER retention, but also type I collagen synthesis and mineralization in human cells from OI patients.

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Section: Discussioncontrasting

confidence: 99%

4-Phenylbutyric acid enhances the mineralization of osteogenesis imperfecta iPSC-derived osteoblasts

Takeyari

Kubota

Ohata

et al. 2021

Journal of Biological Chemistry

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“…In addition, some previous reports showed that erythropoietin (EPO) and hypoxia-inducible factor (HIF) have been associated with vascular calcification. One study reported that EPO attenuates vascular calcification by inhibiting endoplasmic reticulum stress in rats with CKD [40]; meanwhile, other studies have reported that EPO and HIF-1 can promote vascular calcification in CKD, suggesting that inappropriate use of EPO and prolyl HIF-hydroxylase (PH) enzyme (HIF-PH) inhibitors in CKD patients might aggravate vascular calcification and elicit adverse clinical consequences [41,42]. In this study, no significant association between use of ESA and AAC was found.…”

Section: Plos Onecontrasting

confidence: 56%

Association between serum magnesium levels and abdominal aorta calcification in patients with pre-dialysis chronic kidney disease stage 5

et al. 2021

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Background Several studies have revealed the relationship between serum magnesium levels and vascular calcification in chronic kidney disease patients. Despite excellent predictability of abdominal aorta calcification for cardiovascular disease events, the relationship between serum magnesium levels and abdominal aorta calcification, as evaluated by quantitative methods, in pre-dialysis patients remains unclear. This study aimed to determine the abdominal aorta calcification volume using computerized tomography and its association with serum magnesium levels in pre-dialysis chronic kidney disease stage 5 patients. Methods This single-center cross-sectional study included 100 consecutive patients with pre-dialysis chronic kidney disease stage 5 between January 2016 and May 2020 at Aichi Medical University Hospital, Japan. The relationships between serum magnesium levels and the abdominal aorta calcification volume were assessed using multiple linear regression models after adjusting for clinically relevant factors. We also assessed clinical factors that affect serum magnesium levels. Results The mean serum magnesium level was 2.0 mg/dL (interquartile range, 1.8 to 2.3). Multivariate analyses revealed that a higher serum magnesium level (stand. β = -0.245, p = 0.010) was significantly associated with a reduced abdominal aorta calcification volume, and that a history of cardiovascular disease (stand. β = 0.3792, p < 0.001) and older age (stand. β = 0.278, p = 0.007) were significantly associated with an increased abdominal aorta calcification volume. Moreover, multivariate analysis showed that the use of proton pump inhibitor or potassium-competitive acid blocker was significantly associated with lower serum magnesium levels (stand. β = -0.246, p = 0.019). Conclusions The present study revealed that the higher Mg level was significantly associated with lower volume of abdominal aorta calcification in pre-dialysis chronic kidney disease stage 5 patients. Further studies should be undertaken to determine the appropriate magnesium level to suppress vascular calcification.

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“…Studies have indicated that the CKD environment could induce the activation of the PERK-eIF2α-ATF4 signaling pathway, which leads to ER stress and the development of VC. [33,34] Taking into account our current ndings, we aim to reveal the mechanism of potential endorphins protection. terpinen-4-ol against VC.…”

Section: Terpinen-4-ol Alleviates Vc By Inhibiting Perk-eif2α-atf4 Pathway In Vivo and In Vitromentioning

confidence: 99%

The ameliorative effect of terpinen-4-ol on ER stress-induced vascular calcification depends on SIRT1-mediated regulation of PERK acetylation

Zhang

et al. 2021

Pharmacological Research

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BackgroundEndoplasmic reticulum (ER) stress-mediated phenotypic switching of vascular smooth muscle cells (VSMCs) is key to vascular calci cation (VC) in patients with chronic kidney disease (CKD). Terpinen-4-ol exerts protective effect against cardiovascular disease, but its role and speci c mechanism in VC remain unclear. We explored whether terpinen-4-ol alleviates ER stress-mediated VC through sirtuin 1 (sirt1) and elucidated its mechanism to provide evidence for its application in the clinical prevention and treatment of VC. MethodsIn this study, CKD-related VC animal model and β-glycerophosphate (β-GP)-induced VSMCs calci cation model were established. We investigated the part of terpinen-4-ol in ER stress-induced VC in vitro and in vivo. However, in order to clarify whether terpinen-4-ol inhibits the molecular mechanism of ERs-induced VC through sirt1, we further veri ed the above signal transduction by knocking down sirt1 in vitro and in vivo. ResultsTerpinen-4-ol inhibited calcium deposition, phenotypic switching, and ER stress of VSMCs in vitro and in vivo. Furthermore, pre-incubation with terpinen-4-ol or a sirt1 agonist and transfection with lentivirus overexpressing sirt1 decreased β-GP-induced calcium salt deposition, increased sirt1 protein level, and inhibited PERK-eIF2α-ATF4 pathway activation in VSMCs, thus, alleviating VC. The opposite results were obtained in sirt1-knockdown models. Moreover, sirt1 physically interacted with and deacetylated PERK.Mass spectrometry analysis identi ed lysine K889 as the acetylation site of sirt1, which regulates PERK.Finally, inhibition of sirt1 reduced the effect of terpinen-4-ol on the deacetylation of PERK in vitro and in vivo and weakened the inhibitory effect of terpinen-4-ol against ER stress-mediated VC. ConclusionsTerpinen-4-ol inhibits the post-transcriptional modi cation of PERK at the lysine K889 acetylation site by upregulating sirt1 expression level, thereby ameliorating VC by regulating ER stress. This provides evidence of the molecular mechanism of terpinen-4-ol, which supports its development as a promising therapeutic agent for CKD-VC.

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Erythropoietin attenuates vascular calcification by inhibiting endoplasmic reticulum stress in rats with chronic kidney disease

Cited by 19 publications

References 41 publications

4-Phenylbutyric acid enhances the mineralization of osteogenesis imperfecta iPSC-derived osteoblasts

4-Phenylbutyric acid enhances the mineralization of osteogenesis imperfecta iPSC-derived osteoblasts

Association between serum magnesium levels and abdominal aorta calcification in patients with pre-dialysis chronic kidney disease stage 5

The ameliorative effect of terpinen-4-ol on ER stress-induced vascular calcification depends on SIRT1-mediated regulation of PERK acetylation

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