Nitro-oleic acid ameliorates oxygen and glucose deprivation/re-oxygenation triggered oxidative stress in renal tubular cells via activation of Nrf2 and suppression of NADPH oxidase

Huibin NieNephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, PR China; ;Department of Nephrology, Chengdu First People's Hospital, Chengdu, Sichuan, PR China;

Xia XueDepartment of Pharmacy, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, PR China

Gang LiuNephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, PR China;

Guangju GuanNephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, PR China; Correspondence[email protected] [email protected]

Haiying LiuNephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, PR China; Correspondence[email protected] [email protected]

Lina SunNephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, PR China;

Long ZhaoNephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, PR China;

Xueling WangNephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, PR China;

Zhixin ChenNephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, PR China;

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Abstract

Nitroalkene derivative of oleic acid (OA-NO₂), due to its ability to mediate revisable Michael addition, has been demonstrated to have various biological properties and become a therapeutic agent in various diseases. Though its antioxidant properties have been reported in different models of acute kidney injury (AKI), the mechanism by which OA-NO₂ attenuates intracellular oxidative stress is not well investigated. Here, we elucidated the anti-oxidative mechanism of OA-NO₂ in an in vitro model of renal ischemia/reperfusion (I/R) injury. Human tubular epithelial cells were subjected to oxygen and glucose deprivation/re-oxygenation (OGD/R) injury. Pretreatment with OA-NO₂ (1.25 μM, 45 min) attenuated OGD/R triggered reactive oxygen species (ROS) generation and subsequent mitochondrial membrane potential disruption. This action was mediated via up-regulating endogenous antioxidant defense components including superoxide dismutase (SOD1), heme oxygenase 1 (HO-1), and γ-glutamyl cysteine ligase modulatory subunits (GCLM). Moreover, subcellular fractionation analyses demonstrated that OA-NO₂ promoted nuclear translocation of nuclear factor-E2- related factor-2 (Nrf2) and Nrf2 siRNA partially abrogated these protective effects. In addition, OA-NO₂ inhibited NADPH oxidase activation and NADPH oxidase 4 (NOX4), NADPH oxidase 2 (NOX2) and p22^phox up-regulation after OGD/R injury, which was not relevant to Nrf2. These results contribute to clarify that the mechanism of OA-NO₂ reno-protection involves both inhibition of NADPH oxidase activity and induction of SOD1, Nrf2-dependent HO-1, and GCLM.

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Nitro-oleic acid ameliorates oxygen and glucose deprivation/re-oxygenation triggered oxidative stress in renal tubular cells via activation of Nrf2 and suppression of NADPH oxidase

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Nitro-oleic acid ameliorates oxygen and glucose deprivation/re-oxygenation triggered oxidative stress in renal tubular cells via activation of Nrf2 and suppression of NADPH oxidase

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