title: Nox4 has a crucial role in uric acid‑induced oxidative stress and apoptosis in renal tubular cells.
abstract: The purpose of the present study was to evaluate the effects of uric acid in promoting tubular cell apoptosis and verify the role of nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4)‑induced oxidative stress in this process. HK‑2 cells were used as a human proximal tubular cell model and co‑cultured with various concentrations of uric acid with or without pre‑treatment with the Nox4 inhibitor diphenylene iodonium (DPI). The apoptotic rate and the amount of reactive oxygen species (ROS) were examined by flow cytometry. Furthermore, levels of Nox4, phosphorylated (p)‑P38, p‑extracellular signal‑regulated kinase (ERK), B‑cell lymphoma 2 (Bcl‑2) and Bcl‑2‑extra large (Bax) were detected by western blot analysis. The results showed that treatment with uric acid decreased HK‑2 cell viability and promoted apoptosis in a dose‑dependent manner. This was paralleled with an upregulation of Nox4 as well as ROS overproduction, which activated the phosphorylation of P38/ERK and caused an imbalance of Bax/Bcl‑2 in HK‑2 cells. Of note, inhibition of Nox4 with DPI prevented uric acid‑induced cell injury by suppressing ROS generation and P38/ERK activation. In conclusion, it was demonstrated that elevated uric acid promoted ROS‑induced tubular cell apoptosis by upregulating Nox4 expression. The present study therefore provided possible mechanisms and a potential therapeutic target of uric acid‑induced chronic kidney disease.
authors.affiliation: Department of Urology, Sun Yat‑sen Memorial Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510120, P.R. China.
authors.forename: Zhuohang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Urology, Sun Yat‑sen Memorial Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510120, P.R. China.
authors.forename: Yiyu
authors.initials: Y
authors.lastname: Sheng
authors.affiliation: Department of Urology, Sun Yat‑sen Memorial Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510120, P.R. China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Urology, Sun Yat‑sen Memorial Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510120, P.R. China.
authors.forename: Kuiqing
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Urology, Sun Yat‑sen Memorial Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510120, P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Urology, Sun Yat‑sen Memorial Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510120, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Urology, Sun Yat‑sen Memorial Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510120, P.R. China.
authors.forename: Kewei
authors.initials: K
authors.lastname: Xu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007684:Kidney Tubules / Q000201:enzymology*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014527:Uric Acid / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C494826:BAX protein, human; C000595707:BCL2 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D014527:Uric Acid; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D048051:p38 Mitogen-Activated Protein Kinases