The protective role of Nrf2 against aristolochic acid-induced renal tubular epithelial cell injury

Abstract

Aristolochic acid nephropathy is a rapidly progressive tubulointerstitial disease induced by aristolochic acid (AA) and effective treatment is lacking. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been proven to be protective in acute kidney injury and chronic kidney disease progression. But its role in AA-induced renal tubular epithelial cell injury has not been determined. This study aimed to investigate the role of Nrf2 in AA-induced renal tubular epithelial cell injury in vitro. NRK-52E cells were incubated with 5–50 μM AA to evaluate cell viability, reactive oxygen species (ROS) production, cell apoptosis/necrosis, and Nrf2 signaling pathway protein levels. We found that AA reduced cell viability and induced cell apoptosis in a time-dependent manner, accompanied by increased production of intracellular ROS. Meanwhile, the expression of Nrf2 signaling pathway proteins was significantly decreased. Downregulation of Nrf2 by Nrf2 siRNA decreased its downstream antioxidant proteins HO-1 and NQO1 and resulted in increased AA-induced ROS production and cell death. On the contrary, overexpression of Nrf2 increased HO-1 and NQO1 expression and resulted in decreased cell death. In conclusion, Nrf2 plays an important role in AA-induced injury. Enhanced Nrf2 signaling pathway could ameliorate AA-induced renal tubular epithelial cell injury, while downregulation of Nrf2 signaling exacerbated the injury.

Keywords:

• Acute kidney injury
• apoptosis
• aristolochic acid
• Nrf2
• oxidative stress

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the National Natural Science Foundation of China under Grant [81774069, 81570614, 81973602, 81600516]; National Key Research and Development Program under Grant [2016YFC0906101]; Special Fund for NHFPC Scientific Research in Public Welfare under Grant [201502023]; Natural Science Foundation of Guangdong Province under Grant [2014B020212020, 2017A050503003, 2017B020227006]; Foundation of Guangdong Key Laboratory of Nephrology under Grant [2017B030314019]; and Guangzhou Municipal Science and Technology Project under Grant [2014Y2-00543, 201704020167].