Acute nephrotoxicity of aristolochic acids in mice
Acute nephrotoxicity of aristolochic acids in mice
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DOI：
10.1211/0022357023051
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发表时间：
2004-02-01
影响因子：
3.3
通讯作者：
Ueda, S
中科院分区：
文献类型：
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作者：
Sato, N;Takahashi, D;Ueda, S
马兜铃酸（Aristolochic Acids，AA）是马兜铃属植物中的一种有毒物质，可引起中草药肾病（Chinese herbs nephropathy，CHN），一种快速进展的肾小管间质性肾炎（tubulointerstitial nephropathy，TIN）。为了阐明CHN发生的机制，我们尝试用AA诱导小鼠TIN。BALB/c、C3 H/He和C57 BL/6三种近交系小鼠每天腹腔注射或口服AA或AA钠盐（AANa）2.5mg/kg，每周5天，共2周。在处死时获得血清和肾组织。每隔一周在代谢笼中单独采集10小时尿样。在AA注射组中，在BALB/c小鼠中观察到严重的肾小管损伤，出现急性肾小管坏死和罕见的细胞浸润到肾小管中。C3 H/He小鼠也出现TIN，并伴有明显的细胞浸润到结缔组织和间质纤维化。在C57 BU 6小鼠中，仅观察到轻度和局灶性肾小管间质变化。BALB/c和C3 H/He小鼠血清肌酐和血尿素氮升高。免疫荧光研究显示肾脏中无免疫成分沉积。在AANa处理组中，在所有组中也观察到TIN，但腹膜内注射诱导了更严重的肾小管间质变化。进一步用纯化的AAI、AAII、AAIVa和马兜铃内酰胺I（ALI）进行的检测显示，AAI在小鼠中引起强烈的肾毒性，而AAII导致轻度肾毒性。然而，AAIVa和ALI在该实验系统中未引起肾毒性。小鼠对AA肾病的易感性存在品系差异。AAI对小鼠的肾毒性作用最强。
Aristolochic acids (AA), present in Aristolochia plants, are the toxin responsible for Chinese herbs nephropathy (CHN), a rapidly progressive tubulointerstitial nephritis (TIN). To clarify the mechanisms of the development of CHN, we tried to induce TIN in mice using AA. Three strains of inbred mice, BALB/c, C3H/He and C57BL/6, received 2.5 mg kg(-1) of AA or AA sodium salt (AANa) daily by intraperitoneal or oral administration, 5 days a week for 2 weeks. Serum and renal tissue were obtained at sacrifice. Twelve-hour urine samples were individually collected in a metabolic cage at one-week intervals. In the AA-injected groups, severe tubular injury, with the appearance of acute tubular necrosis, and rare cell infiltration into the interstitium, were seen in BALB/c mice. C3H/He mice also developed TIN with prominent cell infiltration into the interstitium and interstitial fibrosis. In C57BU6 mice, only mild and focal tubulointerstitial changes were seen. Serum creatinine and blood urea nitrogen increased in BALB/c and C3H/He mice. Immunofluorescent study revealed no deposition of immune components in kidneys. In the AANa-treated groups, TIN was also seen in all groups, but even more severe tubulointerstitial changes were induced by intraperitoneal injection. Further examination using purified AAI, AAII, AAIVa and aristolactam I (ALI) revealed that AAI induced strong nephrotoxicity in mice, and that AAII resulted in mild nephrotoxicity. However, AAIVa and ALI caused no nephrotoxicity in this experimental system. There are strain differences in mice in their susceptibility to AA nephropathy. AAI exerted the strongest nephrotoxic effect in mice.