Berberine exerts nephroprotective effect against cisplatin-induced kidney damage through inhibition of oxidative/nitrosative stress, inflammation, autophagy and apoptosis

Abstract

The aim of this study was to investigate the therapeutic activity of isoquinoline alkaloid berberine against cisplatin (CP)-induced nephrotoxicity in mice. Berberine was administered at daily doses of 1, 2 and 3 mg/kg by gavage for two successive days, 48 h after intraperitoneal CP injection (13 mg/kg). Mice were sacrificed 24 h after the last dose of berberine. Histopathological changes and the increase in serum creatinine and blood urea nitrogen (BUN) induced by CP were significantly ameliorated by berberine in a dose-dependent manner. Additionally, oxidative/nitrosative stress, evidenced by the increase in renal 4-hydroxynonenal (4-HNE), 3-nitrotyrosine (3-NT), cytochrome P450 E1 (CYP2E1) and heme oxygenase (HO-1) expression, was significantly reduced. The expression of nuclear factor-kappaB (NF-κB), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) was markedly suppressed by berberine, indicating the inhibition of inflammatory response. Treatment of CP-intoxicated animals with berberine also significantly reduced the expression of p53, active caspase-3 as well as autophagy marker light chain 3B (LC3B) in the kidneys. The results of the current study showed the nephroprotective activity of berberine against CP-induced renal injury, which could be attributed to the inhibition of oxidative/nitrosative stress, inflammation, autophagy and apoptosis.

Keywords: 3-NT; 3-nitrotyrosine; 4-HNE; 4-hydroxynonenal; Apoptosis; Autophagy; BUN; Berberine; COX-2; CP; CYP2E1; Cisplatin nephrotoxicity; DMSO; FITC; HE; HO-1; IL; Inflammatory response; LC3; NF-κB; NO(); Oxidative stress; PAS; PVDF; RIPA; TNF-α; TUNEL; blood urea nitrogen; cis-diamineplatinum(II) dichloride; cyclooxygenase-2; cytochrome P450 2E1; dimethyl sulfoxide; fluorescein isothiocyanate; hematoxylin and eosin; heme oxygenase-1; iNOS; inducible nitric oxide synthase; interleukin; light chain 3B; nitric oxide; nuclear factor-kappaB; periodic acid-Schiff; polyvinylidene difluoride; radioimmunoprecipitation assay; terminal deoxynucleotidyl transferase dUTP nick end labeling; tumor necrosis factor-alpha.