School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden, Penang, Malaysia.
Basic Medical Science Department, College of Medicine, Qatar University, Doha, Qatar.
PLoS One. 2020 Apr 16;15(4):e0231472. doi: 10.1371/journal.pone.0231472. eCollection 2020.
Oxidative stress is involved in the pathogenesis of a number of diseases including hypertension and renal failure. There is enhanced expression of nicotinamide adenine dinucleotide (NADPH oxidase) and therefore production of hydrogen peroxide (H2O2) during renal disease progression. This study investigated the effect of apocynin, an NADPH oxidase inhibitor and catalase, an H2O2 scavenger on Cyclosporine A (CsA) nephrotoxicity in Wistar-Kyoto rats. Rats received CsA (25mg/kg/day via gavage) and were assigned to vehicle, apocynin (2.5mmol/L p.o.), catalase (10,000U/kg/day i.p.) or apocynin plus catalase for 14 days. Renal functional and hemodynamic parameters were measured every week, and kidneys were harvested at the end of the study for histological and NADPH oxidase 4 (NOX4) assessment. Oxidative stress markers and blood urea nitrogen (BUN) were measured. CsA rats had higher plasma malondialdehyde (by 340%) and BUN (by 125%), but lower superoxide dismutase and total antioxidant capacity (by 40%, all P<0.05) compared to control. CsA increased blood pressure (by 46mmHg) and decreased creatinine clearance (by 49%, all P<0.05). Treatment of CsA rats with apocynin, catalase, and their combination decreased blood pressure to near control values (all P<0.05). NOX4 mRNA activity was higher in the renal tissue of CsA rats by approximately 63% (P<0.05) compared to controls but was reduced in apocynin (by 64%), catalase (by 33%) and combined treatment with apocynin and catalase (by 84%) compared to untreated CsA rats. Treatment of CsA rats with apocynin, catalase, and their combination prevented hypertension and restored renal functional parameters and tissue Nox4 expression in this model. NADPH inhibition and H2O2 scavenging is an important therapeutic strategy during CsA nephrotoxicity and hypertension.
氧化应激参与了许多疾病的发病机制，包括高血压和肾衰竭。在肾脏疾病进展过程中，烟酰胺腺嘌呤二核苷酸（NADPH 氧化酶）的表达增强，因此产生了过氧化氢（H2O2）。本研究探讨了 NADPH 氧化酶抑制剂 apocynin 和过氧化氢清除剂 catalase 对环孢素 A（CsA）肾病的影响。大鼠每天通过灌胃接受 CsA（25mg/kg），并被分配到载体、apocynin（2.5mmol/L 口服）、catalase（10000U/kg/天腹腔内注射）或 apocynin 加 catalase 组，共 14 天。每周测量肾功能和血液动力学参数，研究结束时采集肾脏进行组织学和 NADPH 氧化酶 4（NOX4）评估。测量氧化应激标志物和血尿素氮（BUN）。与对照组相比，CsA 组大鼠的血浆丙二醛（增加 340%）和 BUN（增加 125%）更高，但超氧化物歧化酶和总抗氧化能力（分别减少 40%，均 P<0.05）。CsA 增加血压（增加 46mmHg）和降低肌酐清除率（减少 49%，均 P<0.05）。用 apocynin、catalase 及其组合治疗 CsA 大鼠可使血压接近对照值（均 P<0.05）。与对照组相比，CsA 大鼠肾组织中 NOX4 mRNA 活性增加约 63%（P<0.05），但用 apocynin（减少 64%）、catalase（减少 33%）和 apocynin 与 catalase 联合治疗（减少 84%）可降低肾组织中的 NOX4 表达。用 apocynin、catalase 及其组合治疗 CsA 大鼠可预防高血压，并恢复该模型的肾功能参数和组织 Nox4 表达。NADPH 抑制和 H2O2 清除是 CsA 肾毒性和高血压治疗的重要策略。
