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VDR activation attenuate cisplatin induced AKI by inhibiting ferroptosis

Cell death & disease, 2020-01, Vol.11 (1), p.73, Article 73 [Peer Reviewed Journal]

This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. ;The Author(s) 2020 ;ISSN: 2041-4889 ;EISSN: 2041-4889 ;DOI: 10.1038/s41419-020-2256-z ;PMID: 31996668

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Title:
VDR activation attenuate cisplatin induced AKI by inhibiting ferroptosis
Author: Hu, Zhaoxin ; Zhang, Hao ; Yi, Bin ; Yang, Shikun ; Liu, Jun ; Hu, Jing ; Wang, Jianwen ; Cao, Ke ; Zhang, Wei
Subjects: 4-Hydroxynonenal ; Acute Kidney Injury - chemically induced ; Acute Kidney Injury - enzymology ; Acute Kidney Injury - genetics ; Acute Kidney Injury - metabolism ; Aldehydes - metabolism ; Animals ; Antineoplastic Agents - toxicity ; Apoptosis ; Cell death ; Cell Death - genetics ; Cell injury ; Cell Line ; Cisplatin ; Cisplatin - toxicity ; Creatinine ; Creatinine - metabolism ; Cyclohexylamines - pharmacology ; Ergocalciferols - pharmacology ; Ferroptosis - drug effects ; Ferroptosis - genetics ; Glutathione peroxidase ; Glutathione Peroxidase - metabolism ; Humans ; Kidneys ; Lipid peroxidation ; Lipid Peroxidation - drug effects ; Male ; Malondialdehyde ; Malondialdehyde - metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microscopy, Electron, Scanning Transmission ; Mitochondria - drug effects ; Mitochondria - metabolism ; Mitochondria - ultrastructure ; Phenotypes ; Phenylenediamines - pharmacology ; Piperazines - metabolism ; Receptors, Calcitriol - agonists ; Receptors, Calcitriol - genetics ; Receptors, Calcitriol - metabolism ; Reporter gene ; RNA, Small Interfering ; siRNA ; Urea ; Vitamin D ; Vitamin D receptors
Is Part Of: Cell death & disease, 2020-01, Vol.11 (1), p.73, Article 73
Description: Our preliminary work has revealed that vitamin D receptor (VDR) activation is protective against cisplatin induced acute kidney injury (AKI). Ferroptosis was recently reported to be involved in AKI. Here in this study, we investigated the internal relation between ferroptosis and the protective effect of VDR in cisplatin induced AKI. By using ferroptosis inhibitor ferrostatin-1 and measurement of ferroptotic cell death phenotype in both in vivo and in vitro cisplatin induced AKI model, we observed the decreased blood urea nitrogen, creatinine, and tissue injury by ferrostatin-1, hence validated the essential involvement of ferroptosis in cisplatin induced AKI. VDR agonist paricalcitol could both functionally and histologically attenuate cisplatin induced AKI by decreasing lipid peroxidation (featured phenotype of ferroptosis), biomarker 4-hydroxynonenal (4HNE), and malondialdehyde (MDA), while reversing glutathione peroxidase 4 (GPX4, key regulator of ferroptosis) downregulation. VDR knockout mouse exhibited much more ferroptotic cell death and worsen kidney injury than wild type mice. And VDR deficiency remarkably decreased the expression of GPX4 under cisplatin stress in both in vivo and in vitro, further luciferase reporter gene assay showed that GPX4 were target gene of transcription factor VDR. In addition, in vitro study showed that GPX4 inhibition by siRNA largely abolished the protective effect of paricalcitol against cisplatin induced tubular cell injury. Besides, pretreatment of paricalcitol could also alleviated Erastin (an inducer of ferroptosis) induced cell death in HK-2 cell. These data suggested that ferroptosis plays an important role in cisplatin induced AKI. VDR activation can protect against cisplatin induced renal injury by inhibiting ferroptosis partly via trans-regulation of GPX4.
Publisher: England: Springer Nature B.V
Language: English
Identifier: ISSN: 2041-4889
EISSN: 2041-4889
DOI: 10.1038/s41419-020-2256-z
PMID: 31996668
Source: Nature Open Access
MEDLINE
PubMed Central
ROAD: Directory of Open Access Scholarly Resources
ProQuest Central
DOAJ Directory of Open Access Journals

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VDR activation attenuate cisplatin induced AKI by inhibiting ferroptosis

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