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.

• Authors: Wei Yan, Yao Xu, Yanhong Yuan, Lei Tian, Qin Wang, Yuanyuan Xie, Xinghua Shao, Ming Zhang, Zhaohui Ni, Shan Mou
• Journal: Free radical research (Free Radic Res) 2017 Jul-Aug Vol. 51 Issue 7-8 Pg. 669-683 ISSN: 1029-2470 [Electronic] England
• PMID: 28750561 (Publication Type: Journal Article)

Chemical References

• Antioxidants
• Interleukin-1beta
• NF-E2-Related Factor 2
• NF-kappa B
• Nfe2l2 protein, mouse
• Reactive Oxygen Species
• Saponins
• Triterpenes
• Tumor Necrosis Factor-alpha
• astragaloside A
• Glutathione Peroxidase
• Heme Oxygenase-1
• Cisplatin

Topics

• Acute Kidney Injury (chemically induced, drug therapy, pathology)
• Animals
• Antioxidants (administration & dosage)
• Cisplatin (adverse effects, therapeutic use)
• Glutathione Peroxidase
• Heme Oxygenase-1 (genetics)
• Inflammation (chemically induced, drug therapy, genetics, pathology)
• Interleukin-1beta
• Kidney (drug effects, pathology)
• Male
• Mice
• NF-E2-Related Factor 2 (genetics)
• NF-kappa B (genetics)
• Oxidative Stress (drug effects)
• Reactive Oxygen Species (metabolism)
• Saponins (administration & dosage)
• Triterpenes (administration & dosage)
• Tumor Necrosis Factor-alpha (genetics)