Penicilliumin B Protects against Cisplatin-Induced Renal Tubular Cell Apoptosis through Activation of AMPK-Induced Autophagy and Mitochondrial Biogenesis

Abstract

Introduction: Acute kidney injury (AKI) is at a high prevalence in hospitalized patients, especially in those receiving chemotherapy. Cisplatin is the most widely used chemotherapy drug; however, with its side effects that include nephrotoxicity, it also exhibits a risk of inducing AKI. Importantly, recent studies have shown that autophagy plays a protective role in cisplatin-induced AKI. However, therapeutic strategies and candidate drugs for inducing activation of autophagy remain limited. Methods: In the present study, we adopted a novel candidate drug from a deep sea-derived Penicillium strain, penicilliumin B, to testify its protective role in cisplatin-induced renal tubular cell injury. Results: Penicilliumin B exhibited protection against cisplatin-induced apoptosis in cultured renal tubular epithelial cells and in cisplatin-treated mice. Moreover, penicilliumin B maintained normal mitochondrial morphology and inhibited the production of mitochondrial reactive oxygen species. Further studies demonstrated that penicilliumin B enhanced autophagic flux, promoted the activation of multiple autophagy-related proteins, such as mTOR, Beclin-1, ATG5, PINK1, and LC3B, and induced the degradation of p62. Interestingly, we also found penicilliumin B triggered phosphorylation of adenosine 5‘-monophosphate-activated protein kinase (AMPK), which is an upstream inducer of nearly all autophagy pathways and also an activator of mitochondrial biogenesis. These results suggest that AMPK may represent an activated site of penicilliumin B. Consistently, compound C, an AMPK inhibitor, significantly blocked the protective effects of penicilliumin B on mitochondria and apoptotic inhibition. Conclusion: Taken together, our findings indicate that penicilliumin B represents a novel AMPK activator that may provide protection against renal tubular cell apoptosis through activation of AMPK-induced autophagy and mitochondrial biogenesis.

Keywords

• apoptosis
• penicilliumin b
• autophagy
• adenosine 5′-monophosphate-activated protein kinase
• cisplatin