Abstract
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.
Highlights
acute kidney injury (AKI) is a common and critical illness which occurs in approximately 5% of hospitalized patients and 30% of critically ill patients and has high morbidity and mortality[1]
Immuohistochemical (IHC) staining of lipid peroxidation marker 4-hydroxynonenal (4HNE) levels showed that cisplatin could tremendously induce the production of 4-hydroxynonenal in renal tubular cells, indicating an aberrant lipid peroxidation during cisplatin induced AKI (cis-AKI)
Ramesh G et al have reported that cisplatin could induce both apoptosis and necrosis which is mediated by TNF receptor 2 (TNFR2) in mice AKI model[17]
Summary
AKI is a common and critical illness which occurs in approximately 5% of hospitalized patients and 30% of critically ill patients and has high morbidity and mortality[1]. Apoptosis and necroptosis were previously reported to be the major pathological processes of acute kidney injury, preclinical works using specific inhibitor of neither apoptosis or necroptosis failed. Indicating that other types of cell death may at least coexists in cisplatin induced AKI. Ferroptosis is a type of “regulated cell death” recently identified as an iron- and lipid hydroperoxide-dependent nonapoptotic cell death in cancer cells[6]. Whether ferroptosis are involved in cisplatin induced AKI (cis-AKI) were not clearly verified yet. In 1998 it was reported that exposure to cisplatin resulted in a significant increase in bleomycindetectable iron in kidney cells and the use of deferoxamine significantly alleviated kidney injury induced by cisplatin in vivo[8]. Our pre-experiments showed that pretreatment of ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, has significantly decreased the blood Urea Nitrogen
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