Renoprotective mechanisms of Astragaloside IV in cisplatin-induced acute kidney injury

Abstract

Nephrotoxicity remains a serious adverse effect of cisplatin chemotherapy, limiting its clinical usage. Numerous studies show that oxidative stress and inflammation are closely associated with cisplatin-induced renal damage. Astragaloside IV (AS-IV) has been found to possess antioxidant and anti-inflammation functions. Therefore, we investigated the potential curative effects of AS-IV against cisplatin-induced renal injury and the possible cellular mechanism for activity, both in vitro and in vivo. We found that pretreatment of HK-2 cells with AS-IV could mitigate cisplatin-induced cell damage caused by oxygen-free radicals and the inflammatory response, as evidenced by reduced formation of reactive oxygen species (ROS) and inflammatory cytokines. AS-IV improved cisplatin-induced renal dysfunction and histopathological injury in mice. Additionally, AS-IV enhanced the activities of total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), and catalase (CAT). It also inhibited cisplatin-induced overproduction of kidney injury molecule-1 (KIM-1), malondialdehyde (MDA), tumour necrosis factor-α (TNF − α), and interleukin-1β (IL-1β) in kidney tissues. We found that the protective effects of AS-IV occurred via activation of the nuclear factor-erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins and inhibition of nuclear factor-κappaB (NF-κB) activation. Further, small interfering RNA (siRNA) knockdown of Nrf2 abrogated the protective effects of AS-IV against cisplatin-induced oxidative stress and blocked the inhibitory effects of AS-IV on cisplatin-induced NF-κB activation and inflammatory cytokine production. In conclusion, our data suggested that AS-IV attenuated cisplatin-mediated renal injury, and these protective effects might be due to inhibition of both oxidative damage and inflammatory response via activation of Nrf2 system and suppression of NF-κB activation.

Keywords:

• Astragaloside IV
• cisplatin
• acute kidney injury (AKI)
• KIM-1
• Nrf2

Acknowledgements

This work was supported by Hong Kong, Macao, and Taiwan Science & Technology Cooperation Program of China under Grant 2014DFT30090; the National Natural Science Foundation of China under Grants 81373865 and 81573748; the Science and Technology Commission of Shanghai Municipality under Grant 14140903200; and the Program of Shanghai Academic Research Leader under Grant 16XD1401900.

Disclosure statement

The authors declare that no conflicts of interest exist.

Additional information

Funding

This work was supported by Hong Kong, Macao, and Taiwan Science & Technology Cooperation Program of China under Grant 2014DFT30090; the National Natural Science Foundation of China under Grants 81373865 and 81573748; the Science and Technology Commission of Shanghai Municipality under Grant 14140903200; and the Program of Shanghai Academic Research Leader under Grant 16XD1401900.