Metformin Protects Against Cisplatin-Induced Tubular Cell Apoptosis and Acute Kidney Injury via AMPKα-regulated Autophagy Induction.

Abstract

Metformin, one of the most common prescriptions for patients with type 2 diabetes, is reported to protect the kidney from gentamicin-induced nephrotoxicity. However, the role and mechanisms for metformin in preventing cisplatin-induced nephrotoxicity remains largely unknown. In this study, a single intraperitoneal injection of cisplatin was employed to induce acute kidney injury (AKI) in CD1 mice. The mice exhibited severe kidney dysfunction and histological damage at day 2 after cisplatin injection. Pretreatment of metformin could markedly attenuate cisplatin-induced acute kidney injury, tubular cell apoptosis and inflammatory cell accumulation in the kidneys. Additionally, pretreatment of metformin could enhance both AMPKα phosphorylation and autophagy induction in the kidneys after cisplatin injection. In cultured NRK-52E cells, a rat kidney tubular cell line, metformin could stimulate AMPKα phosphorylation, induce autophagy and inhibit cisplatin-induced cell apoptosis. Blockade of either AMPKα activation or autophagy induction could largely abolish the protective effect of metformin in cisplatin-induced cell death. Together, this study demonstrated that metformin may protect against cisplatin-induced tubular cell apoptosis and AKI through stimulating AMPKα activation and autophagy induction in the tubular cells.

• Authors: Jianzhong Li, Yuan Gui, Jiafa Ren, Xin Liu, Ye Feng, Zhifeng Zeng, Weichun He, Junwei Yang, Chunsun Dai
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 23975 (Apr 07 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 27052588 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Hypoglycemic Agents
• Protective Agents
• Metformin
• AMPK alpha1 subunit, mouse
• AMP-Activated Protein Kinases
• Cisplatin

Topics

• AMP-Activated Protein Kinases (genetics, metabolism)
• Acute Kidney Injury (chemically induced, metabolism, prevention & control)
• Animals
• Antineoplastic Agents (toxicity)
• Apoptosis (drug effects, genetics)
• Autophagy (drug effects, genetics)
• Blotting, Western
• Cell Line
• Cisplatin (toxicity)
• Hypoglycemic Agents (pharmacology)
• Immunohistochemistry
• Male
• Metformin (pharmacology)
• Mice
• Microscopy, Fluorescence
• Phosphorylation (drug effects)
• Protective Agents (pharmacology)
• RNA Interference
• Rats