Alzu'bi Ayman, Abu-El-Rub Ejlal, Al-Trad Bahaa, Alzoubi Hiba, Abu-El-Rub Hadeel, Albals Dima, Abdelhady Gamal T, Bader Noor S, Almazari Rawan, Al-Zoubi Raed M
Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, 211-63, Jordan.
Department of Biological Sciences, Faculty of Science, Yarmouk University, Irbid, 211-63, Jordan.
Forensic Toxicol. 2025 Jan;43(1):86-96. doi: 10.1007/s11419-024-00699-9. Epub 2024 Aug 9.
The widespread misuse of synthetic cannabinoids (SCs) has led to a notable increase in reported adverse effects, raising significant health concerns. SCs use has been particularly associated with acute kidney injury (AKI). However, the pathogenesis of SCs-induced AKI is not well-understood.
We investigated the nephrotoxic effect of acute administration of N-[(1S)- 1-(aminocarbonyl)-2-methylpropyl]-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide (AB-FUBINKA) (3 mg/kg for 5 days) in mice. Various parameters of oxidative stress, inflammation, and apoptosis have been quantified. The expressions of mitochondrial complexes (I-V) in renal tissues were also assessed.
Our findings showed that AB-FUBINACA induced substantial impairment in the renal function that is accompanied by elevated expression of renal tubular damage markers; KIM-1 and NGAL. Administration of AB-FUBINACA was found to be associated with a significant increase in the expression of oxidative stress markers (iNOS, NOX4, NOX2, NOS3) and the level of lipid peroxidation in the kidney. The expression of pro-inflammatory markers (IL-6, TNF-alpha, NF-kB) was also enhanced following exposure to AB-FUBINACA. These findings were also correlated with increased expression of major apoptosis regulatory markers (Bax, caspase-9, caspase-3) and reduced expression of mitochondrial complexes I, III, and IV.
These results indicate that AB-FUBINACA can trigger oxidative stress and inflammation, and activate caspase-dependent apoptosis in the kidney, with these processes being possibly linked to disruption of mitochondrial complexes and could be an underlying mechanism of SCs-induced nephrotoxicity.
合成大麻素（SCs）的广泛滥用导致报告的不良反应显著增加，引发了重大的健康担忧。SCs的使用尤其与急性肾损伤（AKI）相关。然而，SCs诱导AKI的发病机制尚不清楚。
我们研究了急性给予N-[(1S)-1-(氨基羰基)-2-甲基丙基]-1-[(4-氟苯基)甲基]-1H-吲唑-3-甲酰胺（AB-FUBINKA）（3mg/kg，持续5天）对小鼠的肾毒性作用。对氧化应激、炎症和凋亡的各种参数进行了定量分析。还评估了肾组织中线粒体复合物（I-V）的表达。
我们的研究结果表明，AB-FUBINACA导致肾功能严重受损，同时伴有肾小管损伤标志物KIM-1和NGAL表达升高。发现给予AB-FUBINACA与肾中氧化应激标志物（iNOS、NOX4、NOX2、NOS3）的表达显著增加以及脂质过氧化水平升高有关。暴露于AB-FUBINACA后，促炎标志物（IL-6、TNF-α、NF-κB）的表达也增强。这些结果还与主要凋亡调节标志物（Bax、caspase-9、caspase-3）的表达增加以及线粒体复合物I、III和IV的表达降低相关。
这些结果表明，AB-FUBINACA可引发氧化应激和炎症，并激活肾脏中的caspase依赖性凋亡，这些过程可能与线粒体复合物的破坏有关，可能是SCs诱导肾毒性的潜在机制。
