Department of Physiology, Faculty of Medicine, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, São Paulo 14049-900, Brazil.
Arch Toxicol. 2011 Dec;85(12):1597-606. doi: 10.1007/s00204-011-0717-y. Epub 2011 May 18.
A single injection of adriamycin (ADR) induces marked and persistent proteinuria in rats that progress to glomerular and tubulointerstitial lesions. It has been shown that ADR-induced nephrotoxicity is mediated, at least in part, by oxidative stress that lead to inflammation. Endogenous hydrogen sulfide (H₂S) is synthesized from L-cysteine and is an important signaling molecule in inflammation. This study evaluates the effect of DL-propargylglycine (PAG), an inhibitor of endogenous H₂S formation, on the evolution of renal damage induced by ADR. The rats were injected i.p. with 0.15 M NaCl or PAG (50 mg/kg) 2 h after ADR injection (3.5 mg/kg). Control rats were injected with 0.15 M NaCl or PAG only. Twenty hours urine samples were collected for albuminuria and creatinine measurements on days 1 and 14 after saline or ADR injections and on days 2 and 15 blood samples were collected to measure plasma creatinine, then the rats were killed. The kidneys were removed for H₂S formation evaluation, renal lipid peroxidation and glutathione levels, and histological and immunohistochemical analysis. On day 2 after ADR injection the rats presented increase in oxidative stress associated with neutrophils and macrophages influx in renal tissue. On day 15 the rats also presented increased desmin expression at glomerular edge and vimentin in cortical tubulointerstitium, as well as albuminuria. All these alterations were reduced by PAG injection. The protective effect of PAG on ADR nephrotoxicity was associated to decreased H₂S formation and to restriction of oxidative stress and inflammation in the renal cortex.
阿霉素（ADR）单次注射会导致大鼠出现明显且持久的蛋白尿，并进展为肾小球和肾小管间质损伤。已经表明，ADR 诱导的肾毒性至少部分是由导致炎症的氧化应激介导的。内源性硫化氢（H₂S）是从 L-半胱氨酸合成的，是炎症中的一种重要信号分子。本研究评估了内源性 H₂S 形成抑制剂 DL-炔丙基甘氨酸（PAG）对 ADR 诱导的肾损伤进展的影响。大鼠在 ADR 注射后 2 小时（3.5 mg/kg）通过腹腔注射 0.15 M NaCl 或 PAG（50 mg/kg）。对照组大鼠仅注射 0.15 M NaCl 或 PAG。在注射生理盐水或 ADR 后的第 1 天和第 14 天以及第 2 天和第 15 天收集 20 小时尿液样本，用于白蛋白尿和肌酐测量，并采集血液样本测量血浆肌酐，然后处死大鼠。取出肾脏评估 H₂S 生成、肾脂质过氧化和谷胱甘肽水平，以及进行组织学和免疫组织化学分析。在 ADR 注射后第 2 天，大鼠表现出与中性粒细胞和巨噬细胞在肾组织中浸润相关的氧化应激增加。在第 15 天，大鼠还表现出肾小球边缘的结蛋白表达增加和皮质肾小管间质中的波形蛋白增加，以及白蛋白尿。所有这些改变均通过 PAG 注射得到减轻。PAG 对 ADR 肾毒性的保护作用与 H₂S 形成减少以及肾皮质氧化应激和炎症受限有关。
