Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata-700054, West Bengal, India.
Toxicology. 2010 Jan 31;268(1-2):8-18. doi: 10.1016/j.tox.2009.11.011. Epub 2009 Nov 14.
Acetaminophen (APAP) causes acute and chronic renal failure. The mechanisms leading to hepatic injury have been extensively studied, but the molecular mechanisms regarding APAP-induced nephro-toxicity are poorly defined. In earlier studies, we have demonstrated that arjunolic acid (AA) possesses protective roles against chemically induced organ pathophysiology. The purpose of the present study was to explore whether AA plays any protective role against APAP induced acute renal toxicity; and if so, what pathways it utilizes for the mechanism of its protective action. Exposure of rats with a nephro-toxic dose of APAP altered a number of biomarkers (like blood urea nitrogen and serum creatinine levels, etc.) related to renal oxidative stress, decreased antioxidant activity, elevated renal tumor necrosis factor-alpha and nitric oxide levels. AA treatment both pre- and post to APAP exposure protected the alteration of these biomarkers, compensated deficits in the antioxidant defense mechanisms, and suppressed lipid peroxidation in renal tissue. Investigating the inherent molecular signaling of this pathophysiology and its protection, we found that the mitochondrial pathway was not activated during APAP-induced cell death as no dissipation of mitochondrial membrane potential or release of cytochrome C was detected in the respective experiments. Our experimental evidence suggests that APAP-induced nephro-toxicity is a caspase-dependent process that involves activation of caspase-9 and caspase-3 in the absence of cytosolic cytochrome C release. These results provide evidence that inhibition of NO overproduction and maintenance of intracellular antioxidant status may play a pivotal role in the protective effects of AA against APAP-induced renal damage. AA represents a potential therapeutic option to protect renal tissue from the detrimental effects of acute acetaminophen overdose.
对乙酰氨基酚（APAP）可导致急性和慢性肾衰竭。人们已经对导致肝损伤的机制进行了广泛研究，但对 APAP 诱导的肾毒性的分子机制仍知之甚少。在早期的研究中，我们已经证明，熊果酸（AA）具有针对化学诱导的器官病理生理学的保护作用。本研究的目的是探讨 AA 是否对 APAP 诱导的急性肾毒性具有保护作用；如果是，它利用哪些途径发挥其保护作用。用肾毒性剂量的 APAP 暴露大鼠会改变许多与肾氧化应激相关的生物标志物（如血尿素氮和血清肌酐水平等），降低抗氧化活性，增加肾肿瘤坏死因子-α和一氧化氮水平。AA 治疗可预防 APAP 暴露后这些生物标志物的改变，补偿抗氧化防御机制的缺陷，并抑制肾组织中的脂质过氧化。研究这种病理生理学及其保护作用的内在分子信号，我们发现线粒体途径在 APAP 诱导的细胞死亡过程中没有被激活，因为在各自的实验中没有检测到线粒体膜电位的耗散或细胞色素 C 的释放。我们的实验证据表明，APAP 诱导的肾毒性是一种依赖半胱天冬酶的过程，在没有细胞质细胞色素 C 释放的情况下，涉及半胱天冬酶-9 和半胱天冬酶-3 的激活。这些结果表明，抑制 NO 过度产生和维持细胞内抗氧化状态可能在 AA 对抗 APAP 诱导的肾损伤的保护作用中发挥关键作用。AA 代表了一种潜在的治疗选择，可以保护肾脏组织免受急性对乙酰氨基酚过量的有害影响。
