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

ABSTRACT

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 factor­κB (NF­κB) and mitogen­activated 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 cisplatin­induced renal injury have remained elusive. The present study investigated the effects of PYP on cisplatin­induced nephrotoxicity in the HK2 human proximal tubular epithelial cell line. PYP treatment reduced cisplatin­induced apoptosis and death of HK2 cells by restoring the B­cell lymphoma­2 (Bcl­2)­associated X protein (Bax)/Bcl­2 imbalance, cytochrome c release and caspase­3 activation. In addition, PYP activated the redox­sensitive transcription factor NF­κB 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 2­related factor 2 in HK2 cells. PYP markedly attenuated cisplatin­induced p38, MAPK and c­Jun N­terminal kinase phosphorylation. Furthermore, treatment with PYP ameliorated cisplatin­induced renal cell damage by upregulating antioxidant defense mechanisms and downregulating the MAPK and NF­κB 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 cisplatin­induced 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 interleukin­6 (IL­6), IL­1ß, tumor necrosis factor­α and monocyte chemoattractant protein­1 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 NF­κB signaling pathways and the mRNA levels of inflammatory genes.