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

Sci Rep. 2016 Apr 7;6:23975. doi: 10.1038/srep23975.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Acute Kidney Injury / chemically induced
  • Acute Kidney Injury / metabolism
  • Acute Kidney Injury / prevention & control*
  • Animals
  • Antineoplastic Agents / toxicity
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Autophagy / drug effects*
  • Autophagy / 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

Substances

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