Protein extracted from Porphyra yezoensis prevents cisplatin-induced nephrotoxicity by downregulating the MAPK and NF-B pathways

摘要

Acute renal failure is a serious complication of treatment with the anticancer drug cisplatin. Cisplatin exerts a cytotoxic effect on renal cells by inducing apoptosis through activating the tumor suppressor p53, nuclear factor-B (NF-B) and mitogen-activated protein kinase (MAPK)/p38 pathways. Effects of protein extracts of the brown seaweed Porphyra yezoensis (P. yezoensis) on cytotoxicity, inflammation and cell proliferation have been reported; however, the effects of P. yezoensis protein (PYP) extract on cisplatin-induced renal injury have remained elusive. The present study investigated the effects of PYP on cisplatin-induced nephrotoxicity in the HK2 human proximal tubular epithelial cell line. PYP treatment reduced cisplatin-induced apoptosis and death of HK2 cells by restoring the B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax)/Bcl-2 imbalance, cytochrome c release and caspase-3 activation. In addition, PYP activated the redox-sensitive transcription factor NF-B via stimulating the nuclear translocation of p65 in HK2 cells. PYP also restored renal antioxidant levels and increased the total and nuclear accumulation of NF erythroid 2-related factor 2 in HK2 cells. PYP markedly attenuated cisplatin-induced p38, MAPK and c-Jun N-terminal kinase phosphorylation. Furthermore, treatment with PYP ameliorated cisplatin-induced renal cell damage by upregulating antioxidant defense mechanisms and downregulating the MAPK and NF-B signaling pathways. In addition, mice were divided into three treatment groups (control, cisplatin and PYP + cisplatin) and the effects of PYP were evaluated in a mouse model of cisplatin-induced acute kidney injury. The concentrations of blood urea nitrogen and serum creatinine in the PYP + cisplatin group were lower than those in the cisplatin group. The mRNA expression levels of inflammatory factors interleukin-6 (IL-6), IL-1, tumor necrosis factor- and monocyte chemoattractant protein-1 in the kidney tissues of the PYP + cisplatin group were also lower than those in the cisplatin group. These results suggest that PYP treatment had a preventive effect on nephrotoxicity, specifically by downregulating the MAPK and NF-B signaling pathways and the mRNA levels of inflammatory genes.