Abdelrahman Rehab S, Abdelsalam Ramy A, Zaghloul Marwa S
Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
J Biochem Mol Toxicol. 2022 May;36(5):e23011. doi: 10.1002/jbt.23011. Epub 2022 Feb 22.
Acute kidney injury (AKI) is a complex syndrome associated with a decrease in renal function and a significant impact on patient outcomes. Injection of folic acid (FA) in mice is used for studying the pathogenesis of AKI. This study investigated the impact of trimetazidine (a metabolic modulator-antianginal drug; TMZ), against FA-induced AKI. AKI was induced by FA (250 mg/kg, ip) in mice. Two doses of TMZ were administered orally for 10 days. Administration of TMZ at a high dose (20 mg/kg) exhibited significant decreases in the renal somatic index (RSI), serum levels of lactate dehydrogenase (LDH), creatinine (Cr), blood urea nitrogen (1), and proteins level in urine. Moreover, TMZ significantly increased creatinine clearance (CCr), serum albumin, urine creatinine, and urine urea levels. This improvement in markers of kidney damage was associated with marked renal antioxidant effects (↓NO and ↓lipid peroxidation, normalized reduced glutathione (GSH) level and superoxide dismutase (SOD) activity, and increased HIF-1α/HO-1 level). Furthermore, TMZ significantly decreased FA-induced expression of MPO and inflammatory cytokine IL-18, TNF-α, and NF-κB p65 subunit. Renal apoptosis, along with apoptotic markers, were enhanced by FA injection and suppressed by TMZ administration (↓Caspase-3, ↓Bax, and ↑Bcl2 expression). Finally, TMZ amended FA-induced histopathological changes in kidneys. By mitigating functional alteration, oxidative stress, and preventing the development of inflammatory and apoptosis signals, TMZ provides dose-dependent defense against FA-induced AKI mainly via stimulation of hypoxia-inducible factor-1 alpha (HIF-1α)/heme oxygenase-1 (HO-1) pathway.
急性肾损伤（AKI）是一种与肾功能下降相关的复杂综合征，对患者预后有重大影响。在小鼠中注射叶酸（FA）用于研究AKI的发病机制。本研究调查了曲美他嗪（一种代谢调节剂 - 抗心绞痛药物；TMZ）对FA诱导的AKI的影响。通过给小鼠腹腔注射FA（250 mg/kg）诱导AKI。口服给予两剂量的TMZ，持续10天。高剂量（20 mg/kg）的TMZ给药使肾脏体质量指数（RSI）、血清乳酸脱氢酶（LDH）、肌酐（Cr）、血尿素氮（1）水平以及尿蛋白水平显著降低。此外，TMZ显著增加了肌酐清除率（CCr）、血清白蛋白、尿肌酐和尿尿素水平。肾脏损伤标志物的这种改善与显著的肾脏抗氧化作用相关（降低NO和脂质过氧化，使还原型谷胱甘肽（GSH）水平和超氧化物歧化酶（SOD）活性恢复正常，以及增加缺氧诱导因子 - 1α（HIF - 1α）/血红素加氧酶 - 1（HO - 1）水平）。此外，TMZ显著降低了FA诱导的髓过氧化物酶（MPO）以及炎性细胞因子白细胞介素 - 18（IL - 18）、肿瘤坏死因子 - α（TNF - α）和核因子 - κB p65亚基的表达。FA注射增强了肾细胞凋亡及其凋亡标志物，而TMZ给药则抑制了这种情况（降低半胱天冬酶 - 3（Caspase - 3）、降低Bax并增加Bcl2表达）。最后，TMZ改善了FA诱导的肾脏组织病理学变化。通过减轻功能改变、氧化应激以及预防炎症和凋亡信号的发展，TMZ主要通过刺激缺氧诱导因子 - 1α（HIF - 1α）/血红素加氧酶 - 1（HO - 1）途径提供剂量依赖性防御，抵抗FA诱导的AKI。
