Kalaycı Rivaze, Bingül İlknur, Soluk-Tekkeşin Merva, Olgaç Vakur, Bekpınar Seldağ, Uysal Müjdat
Department of Laboratory Animals Science, Aziz Sancar Institude of Experimental Medicine, Istanbul University, Istanbul, Turkey.
Department of Medical Biochemistry, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
Drug Chem Toxicol. 2024 Jul;47(4):473-482. doi: 10.1080/01480545.2023.2219036. Epub 2023 Jun 20.
Cyclosporine A (CsA) is an immunosuppressive drug, used in organ transplantations. Oxidative stress, inflammation and renin-angiotensin system (RAS) activation play an important role in CsA-toxicity. Glycine (Gly) has antioxidant and anti-inflammatory effects. In this study, Gly was investigated for its protective role against CsA-induced toxicity. CsA (20 mg/kg/day; subcutaneously) was administered to rats along with Gly injection (250 or 1000 mg/kg; intraperitoneally) for 21 days. Renal function markers [serum urea and creatinine and urinary protein and kidney injury molecule levels and creatinine clearance values] together with histopathological examinations were performed. Oxidative stress (reactive oxygen species, thiobarbutiric acid reactive substances, advanced oxidation products of protein, glutathione, ferric reducing anti-oxidant power and 4-hydroxynonenal levels), and inflammation (myeloperoxidase activity) were determined in kidney tissue. The RAS system [angiotensin II (Ang II) levels, and mRNA expressions of angiotensin converting enzyme (ACE), angiotensin II type-I receptor (AT1R)] and NADPH-oxidase 4 (NOX4) were measured in kidney and aorta. CsA caused significant disturbances in renal function markers, increases in oxidative stress and inflammation parameters and renal damage. Serum angiotensin II levels and mRNA expressions of ACE, AT1R and NOX4 elevated in the aorta and kidney of CsA-rats. Gly, especially its high-dose, alleviated renal function markers, oxidative stress, inflammation and renal damage in CsA-rats. Moreover, serum Ang II levels and mRNA expressions of ACE, AT1R and NOX4 decreased significantly in aorta and kidney in CsA-rats due to Gly treatment. Our results indicate that Gly may be useful for the prevention of CsA-induced renal and vascular toxicity.
环孢素A（CsA）是一种免疫抑制药物，用于器官移植。氧化应激、炎症和肾素-血管紧张素系统（RAS）激活在CsA毒性中起重要作用。甘氨酸（Gly）具有抗氧化和抗炎作用。在本研究中，研究了Gly对CsA诱导毒性的保护作用。将CsA（20mg/kg/天；皮下注射）与Gly注射（250或1000mg/kg；腹腔注射）一起给予大鼠，持续21天。进行了肾功能标志物[血清尿素、肌酐、尿蛋白、肾损伤分子水平和肌酐清除率值]以及组织病理学检查。测定了肾组织中的氧化应激（活性氧、硫代巴比妥酸反应性物质、蛋白质的晚期氧化产物、谷胱甘肽、铁还原抗氧化能力和4-羟基壬烯醛水平）和炎症（髓过氧化物酶活性）。测定了肾和主动脉中的RAS系统[血管紧张素II（Ang II）水平、血管紧张素转换酶（ACE）、血管紧张素II 1型受体（AT1R）的mRNA表达]和NADPH氧化酶4（NOX4）。CsA导致肾功能标志物出现显著紊乱，氧化应激和炎症参数增加以及肾损伤。CsA处理大鼠的主动脉和肾脏中血清血管紧张素II水平以及ACE、AT1R和NOX4的mRNA表达升高。Gly，尤其是高剂量的Gly，减轻了CsA处理大鼠的肾功能标志物、氧化应激、炎症和肾损伤。此外，由于Gly处理，CsA处理大鼠的主动脉和肾脏中血清Ang II水平以及ACE、AT1R和NOX4的mRNA表达显著降低。我们的结果表明，Gly可能有助于预防CsA诱导的肾和血管毒性。
