Apigenin ameliorates doxorubicin-induced renal injury via inhibition of oxidative stress and inflammation.

Abstract

BACKGROUND AND OBJECTIVE:

Doxorubicin (DOX) is an anthracycline antitumor antibiotic widely utilized in treating various tumors. Nevertheless, the toxicity of DOX toward normal cells limits its applicability, with nephrotoxicity considered a major dose-limiting adverse effect. Apigenin (APG), a flavonoid widely distributed in natural plants, has been reported to have antioxidant, anti-inflammatory, and mild tumor-suppressive properties. In this study, we investigated the role of APG in DOX-induced nephrotoxicity and chemotherapeutic efficacy.

METHODS:

Male BALB/c mice were administered DOX (11.5 mg/kg) via the tail vein to establish the DOX nephropathy model. After treatment with or without APG (125, 250, and 500 mg/kg) for two weeks, urine, serum, and tissue samples were collected to evaluate proteinuria, serum albumin, serum creatinine (Scr), blood urea nitrogen (BUN), superoxide dismutase (SOD) activity, malondialdehyde (MDA), glutathione (GSH), and pathological changes. Rat renal tubular epithelial cells (NRK52E), murine podocyte cells (MPC5), and murine breast cancer cells (4T1) were utilized to verify the effect of APG on DOX-induced cell injury. An MTT assay was employed to analyze cell viability. Apoptosis was evaluated using a colorimetric TUNEL staining and cleaved caspase-3 protein analysis by western blotting. A reactive oxygen species (ROS)/superoxide (O2-) fluorescence probe was employed to determine oxidative injury. Western blotting was used to analyze nephrin, α-smooth muscle actin (α-SMA), collagen I (Col1), fibronectin (FN), and SOD2 expression. The mRNA levels of tumor necrosis factor-α (TNF-α), interleukin-18 (IL-18), IL-6, NACHT, LRR, PYD domain-containing protein 3 (NLRP3), caspase-1, and IL-1β were tested by reverse transcription-polymerase chain reaction (RT-PCR).

RESULTS:

APG ameliorated DOX-elicited renal injuries in both the glomeruli and tubules. The DOX + APG groups had much lower tissue MDA, IL-6, TNF-α, NLRP3, caspase-1, and IL-1β levels and generation of intracellular ROS, but significantly higher SOD activity and GSH levels compared to those of the DOX group. Additionally, APG attenuated DOX-induced morphological changes, loss of cellular viability, and apoptosis in NRK-52E and MPC-5 cells, but not in 4T1 cells.

CONCLUSION:

APG has a protective role against DOX-induced nephrotoxicity, without weakening DOX cytotoxicity in malignant tumors. Thus, APG may serve as a potential protective agent against renal injury and inflammatory diseases and may be a promising candidate to attenuate renal toxicity in cancer patients treated with DOX.

• Authors: Qijing Wu, Wei Li, Jing Zhao, Wei Sun, Qianqian Yang, Chong Chen, Ping Xia, Jingjing Zhu, Yiceng Zhou, Guoshun Huang, Chen Yong, Min Zheng, Enchao Zhou, Kun Gao
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 137 Pg. 111308 (May 2021) ISSN: 1950-6007 [Electronic] France
• PMID: 33556877 (Publication Type: Journal Article)
• Copyright: Published by Elsevier Masson SAS.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antibiotics, Antineoplastic
• Antioxidants
• Reactive Oxygen Species
• Apigenin
• Doxorubicin

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology, therapeutic use)
• Antibiotics, Antineoplastic
• Antioxidants (pharmacology, therapeutic use)
• Apigenin (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Line, Tumor (drug effects)
• Doxorubicin
• Kidney Diseases (chemically induced, pathology, prevention & control)
• Kidney Function Tests
• Kidney Glomerulus (pathology)
• Kidney Tubules (pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Oxidative Stress (drug effects)
• Rats
• Reactive Oxygen Species