Abstract
Background: Cisplatin is a widely used chemotherapeutic drug, whereas the clinical application is greatly limited by its nephrotoxic side effect. Currently, there has been no effective treatment to prevent cisplatin-induced acute kidney injury (cisplatin-AKI). Human amniotic epithelial cells (hAECs) and their derived exosomes (EXOs) have been proven to effectively protect against ischemia reperfusion-induced AKI, yet their roles in cisplatin-AKI are still unknown. Methods: C57BL/6J mice were given two doses of cisplatin at 20 or 15 mg/kg of body weight to induce AKI with or without mortality. hAECs or EXOs were injected via tail vein 1 day after cisplatin administration. Serum and kidney tissues were collected on the fourth day after 15 mg/kg cisplatin treatment to explore the nephro-protective effects of hAECs and EXOs on cisplatin-AKI. Lung cancer xenograft model was built by subcutaneous injection of A549 cells into BALB/c nude mice to evaluate the effect of hAECs or EXOs on cisplatin chemotherapy. Results: Cisplatin nephrotoxicity was significantly attenuated by hAECs and EXOs as evidenced by reduced mortality rate and decreased serum creatinine (sCr) and reduced tubular injury score. hAECs or EXOs exerted the nephro-protective effects via suppression of TNF-α/MAPK and caspase signaling pathways. In the A549 lung cancer xenograft mouse model, administration of hAECs or EXOs did not promote tumor growth or compromise the therapeutic effects of cisplatin on tumors. Conclusion: This study is the first to demonstrate that hAECs and their derived exosomes have nephro-protective effects in cisplatin-AKI in vivo. Importantly, neither hAECs nor EXOs compromise the antitumor activity of cisplatin. These results potentially support the use of hAECs and their derived EXOs as nephro-protectors against cisplatin-induced nephrotoxicity clinically.
Highlights
Acute kidney injury (AKI) is defined as an abrupt decrease in kidney function within hours, which encompasses structural damage of the kidney and loss of renal function (Makris and Spanou, 2016)
To establish the roles of Human amniotic epithelial cells (hAECs) and their derived EXOs in cisplatin acute nephrotoxicity, we examined the mortality, renal function, and renal tissue damage in cisplatin-AKI mice with hAECs or EXOs administration 1 day post cisplatin injection
The 6-day mortality rate in high-dose cisplatin (20 mg/kg)-treated group reached to 100%, while hAECs or EXOs administration significantly decreased the 6-day mortality rate to 50% (Figure 1A)
Summary
Acute kidney injury (AKI) is defined as an abrupt decrease in kidney function within hours, which encompasses structural damage of the kidney and loss of renal function (Makris and Spanou, 2016). The nephrotoxic side effects of cisplatin greatly restrict its clinical application (Volarevic et al, 2019). Cisplatin accumulates in renal proximal tubular cells, resulting in inflammation, injury, and cell death (Holditch et al, 2019). There is an urgent need for the clinical application of safe and efficacious nephro-protective therapy for cisplatin-treated patients (Motwani et al, 2018). Cisplatin is a widely used chemotherapeutic drug, whereas the clinical application is greatly limited by its nephrotoxic side effect. There has been no effective treatment to prevent cisplatin-induced acute kidney injury (cisplatin-AKI). Human amniotic epithelial cells (hAECs) and their derived exosomes (EXOs) have been proven to effectively protect against ischemia reperfusion-induced AKI, yet their roles in cisplatin-AKI are still unknown
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