Abstract
Cisplatin is extensively used and is highly effective in clinical oncology; nevertheless, nephrotoxicity has severely limited its widespread utility. Isoquercitrin (IQC), a natural flavonoid widely found in herbage, is well known and recognized for its antioxidant, anti-inflammatory, and anti-apoptotic properties. However, the potential effects and mechanism of IQC in cisplatin-induced acute kidney diseases remain unknown. In this study, we postulated the potential effects and mechanism of IQC upon cisplatin exposure in vivo and in vitro. For the in vivo study, C57BL/6J mice were pretreated with IQC or saline (50 mg/kg/day) by gavage for 3 days before cisplatin single injection (25 mg/kg). Renal function, apoptosis, inflammation, oxidative stress and p-ERK were measured to evaluate kidney injury. In vitro, mouse proximal tubular cells (mPTCs) and human proximal tubule epithelial cell line (HK2) were pretreated with or without IQC (80 μM for mPTCs and 120 μM for HK2) for 2 h and then co-administrated with cisplatin for another 24 h. Apoptosis, inflammation, ROS and p-ERK of cells were also measured. In vivo, IQC administration strikingly reduced cisplatin-induced nephrotoxicity as evidenced by the improvement in renal function (serum creatinine and blood urea nitrogen), kidney histology (PAS staining), apoptotic molecules (cleaved caspase-3, caspase-8, Bax and Bcl-2), inflammatory cytokines (IL-1β, IL-6, TNF-α, and COX-2), oxidative stress (MDA and total glutathione) and p-ERK. In line with in vivo findings, IQC markedly protected against cisplatin-induced cell injury in mPTCs and HK2 cells. Collectively, these findings demonstrated that IQC administration could significantly protect against cisplatin nephrotoxicity possibly through ameliorating apoptosis, inflammation and oxidative stress accompanied by cross talk with p-ERK. Furthermore, IQC may have potential therapeutic uses in the treatment of cisplatin-induced acute kidney injury.
Highlights
Cisplatin (cis-diamminedichloroplatinum (II), CDDP) is used in many chemotherapy regimens due to its prominent and broadspectrum antineoplastic characteristics
Consistent with the improved kidney function, concomitant IQC treatment exerted a protective effect on cisplatin-treated renal histopathological damage and preserved the renal architecture by staining with Periodic AcidSchiff (PAS)
It shows that the vehicle group (Vehicle) group exhibited normal, intact kidney morphology, while the Vehicle + cisplatin alone group (Cis) group was characterized by severe alterations such as brush border loss, vacuolization, tubular cell necrosis, luminal dilatation, and cast formation
Summary
Cisplatin (cis-diamminedichloroplatinum (II), CDDP) is used in many chemotherapy regimens due to its prominent and broadspectrum antineoplastic characteristics. There are multi-factorial mechanisms for cisplatin-induced nephrotoxicity including reactive oxidative stress (ROS), reactive nitrogen species, inflammation, apoptosis, fibrogenesis, necrosis and hypoxia (Yao et al, 2007). No effective and conclusive therapy is available that can block cisplatin-induced nephrotoxicity. In this context, the uses of antiapoptotic, antiinflammatory, and antioxidant agents have become primary approaches to develop therapeutic strategies to inhibit or at least reduce cisplatin-induced nephrotoxicity. Combinatorial regimens of herbage have been gaining increasing interest to reduce the side effects of cisplatin. W. et al, 2019; Ma et al, 2019; Wahdan et al, 2019) have demonstrated a potential of regimens of herbage in protecting against the cisplatin nephrotoxicity
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