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

Weiwei Shen; Nan Jia; Jinhua Miao; Shuangqin Chen; Shan Zhou; Ping Meng; Xuefeng Zhou; Lan Tang; Lili Zhou

doi:10.1159/000514657

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

Kidney Dis (Basel). 2021 Jul;7(4):278-292. doi: 10.1159/000514657. Epub 2021 Apr 1.

Authors

Weiwei Shen¹, Nan Jia¹, Jinhua Miao¹, Shuangqin Chen¹, Shan Zhou¹, Ping Meng¹, Xuefeng Zhou², Lan Tang³, Lili Zhou^{1

4}

Affiliations

¹ State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
² Chinese Academy of Sciences (CAS) Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, CAS, Guangzhou, China.
³ Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
⁴ Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.

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: Adenosine 5′-monophosphate-activated protein kinase; Apoptosis; Autophagy; Cisplatin; Penicilliumin B.