Abstract

Cisplatin is the most widely used chemotherapeutic agent. However, it often causes nephrotoxicity, which results in acute kidney injury (AKI). Therefore, we urgently need a drug that can reduce the nephrotoxicity induced by cisplatin. Loganin is a major iridoid glycoside isolated from Corni fructus that has been used as an anti-inflammatory agent in various pathological models. However, the renal protective activity of loganin remains unclear. In this study, to examine the protective effect of loganin on cisplatin-induced AKI, male C57BL/6 mice were orally administered with loganin (1, 10, and 20 mg/kg) 1 h before intraperitoneal injection of cisplatin (10 mg/kg) and sacrificed at three days after the injection. The administration of loganin inhibited the elevation of blood urea nitrogen (BUN) and creatinine (CREA) in serum, which are used as biomarkers of AKI. Moreover, histological kidney injury, proximal tubule damages, and renal cell death, such as apoptosis and ferroptosis, were reduced by loganin treatment. Also, pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, reduced by loganin treatment. Furthermore, loganin deactivated the extracellular signal-regulated kinases (ERK) 1 and 2 during AKI. Taken together, our results suggest that loganin may attenuate cisplatin-induced AKI through the inhibition of ERK1/2.

Highlights

  • Cisplatin is widely used for the treatment of malignant tumors in the head and neck, lungs, ovaries, and the bladder [1]

  • Consistent with previous reports [25,26], our results show that serum blood urea nitrogen (BUN) and CREA were significantly elevated in the cisplatin-induced acute kidney injury (AKI) model

  • We found that glutathione peroxidase 4 (GPX4) was significantly downregulated, and 4-HNE was upregulated during AKI, in accordance with previous reports [33,34], which suggests ferroptosis is well-established in our AKI model

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Summary

Introduction

Cisplatin is widely used for the treatment of malignant tumors in the head and neck, lungs, ovaries, and the bladder [1]. The cytotoxic activity of cisplatin against tumor cells mainly involves cross-linked purine bases within the DNA, and it interferes with DNA synthesis and induces apoptosis [2]. Cisplatin induces several side effects, such as hepatotoxicity [3,4], cardiotoxicity [5,6], gastrotoxicity [7], ototoxicity [8,9], and nephrotoxicity [10,11,12]. Nephrotoxicity is a frequent and major complication of cisplatinbased chemotherapy; it can cause acute kidney injury (AKI) mediated by apoptosis of renal proximal tubule cells [12].

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