VDR activation attenuate cisplatin induced AKI by inhibiting ferroptosis

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.

Mechanisms of Cisplatin-Induced Acute Kidney Injury: Pathological Mechanisms, Pharmacological Interventions, and Genetic Mitigations

“…Studies have determined the use of natural antioxidants including, vitamin C [97], vitamin E [98], and activation of the vitamin D receptor [43] to target ROS formation, which have all shown nephroprotective properties against renal toxicity [15]. The beneficial co-therapy of cisplatin and vitamin C in C57BL/6 mice has been previously demonstrated.…”

Ferroptosis in Acute Central Nervous System Injuries: The Future Direction?

“…Moreover, ferroptosis regulation may be useful for anti-cancer therapy ( Guo et al, 2019 ; Su et al, 2020 ). Although ferroptosis was first defined in cancer cells and has potential in cancer treatment, the latest experimental results have identified its role in the pathophysiology of acute organ injuries, such as acute kidney, lung, and brain injuries ( Dixon et al, 2012 ; Friedmann Angeli et al, 2014 ; Kenny et al, 2019 ; Hu et al, 2020 ; Li Y.C. et al, 2020 ).…”

Neuroprotective Effects of the Anti-cancer Drug Lapatinib Against Epileptic Seizures via Suppressing Glutathione Peroxidase 4-Dependent Ferroptosis

“…To further investigate the potential molecular mechanism by which lapatinib exerted neuroprotection, the alterations of ferroptosisrelated indices including 4-HNE (a common by-product of lipid peroxidation) (Hu et al, 2020) and PTGS2 (a potential molecular marker of ferroptosis) (Jiang, 2015) were detected in our present investigation. 4-HNE was the protein adducts that correspond to the dominant bands including 76, 52, and 17 KDa.…”