环境镉暴露致肾功能损伤:TGF-β1/Smad3及其相关微小RNA的作用
Renal impairment induced by environmental cadmium exposure: Role of TGF-β1/Smad3 and related microRNAs
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摘要:
背景 镉是一种重要的环境污染物，低剂量环境镉暴露能够对机体产生健康损伤。肾脏是镉毒性作用重要的靶器官之一，但目前关于镉暴露致肾损伤的机制尚不清楚。
目的 探讨低剂量环境镉暴露与外周血转化生长因子（TGF）-β1/Smad3、相关微小RNA（miRNA）和肾损伤的关系。
方法 选择有污染灌溉史的某社区居民223人为暴露组，选择与该社区相距约32 km无污染灌溉史的某社区居民237人为对照组。采用面对面问卷调查的形式收集镉暴露区和非镉暴露区居民的一般情况；采集空腹静脉血检测血浆TGF-β1及Smad3，采集尿液检测尿N-乙酰-β-葡萄糖苷酶（UNAG）、尿白蛋白（UALB）、尿肾损伤因子1（UKim-1）以及尿镉水平。分析尿镉与血浆TGF-β1/Smad3及肾功能指标的关系。通过1：1匹配的病例对照研究设计在镉接触肾损伤组和对照组中比较血浆TGF-β1/Smad3相关miRNA的表达水平。
结果 暴露组人群尿镉的总体水平为1.06μg/g（以肌酐校正，余同），高于对照组（0.74μg/g）（P < 0.001）。此外，镉暴露组血浆TGF-β1、血浆Smad3、UNAG和UALB水平均高于对照组（均P < 0.05）。暴露组UNAG和UALB的水平以及对照组UNAG和UKim-1水平均随年龄增加而增加（均P趋势 < 0.01）。Pearson相关分析结果显示，血浆TGF-β1水平与UNAG、血浆Smad3水平呈正相关关系（r=0.133，P < 0.001；r=0.091，P < 0.05）。回归分析结果显示，UNAG（b=0.285，95% CI：0.076~0.494）、UALB（b=0.738，95% CI：0.385~1.092）和UKim-1（b=0.038，95% CI：0.014~0.062）的变化与尿镉关系密切。镉暴露且肾损伤组miRNA-21、miRNA-192和miRNA-126的表达水平均高于对照组（均P < 0.001）。
结论 环境镉暴露人群血浆TGF-β1、Smad3水平增加，miRNA-21、miRNA-192和miRNA-126表达水平的增加与镉暴露相关肾损伤可能有关。
Abstract:Background Cadmium is a major environmental pollutant, and can induce damage to human health at low levels. Kidney is one of the target organs of cadmium. However, the mechanism of renal impairment caused by cadmium exposure is not clear yet.
Objective This study is designed to evaluate the relationship of low-level environmental cadmium exposure with plasma transforming growth factor (TGF)-β1/Smad3, related microRNAs (miRNA), and kidney injury.
Methods A total of 223 community residents from a village irrigated with cadmium polluted water were selected as exposed group, and 237 community residents from a village 32 km away from the polluted area and not irrigated with cadmium polluted water were selected as control group. A face-to-face questionnaire survey was conducted to collect general information of the residents from cadmium polluted and non-polluted areas. Fasting venous blood samples were collected to detect plasma TGF-β1 and Smad3, and urinary samples were also collected to detect urinary N-acetyl-beta-D-glucosaminidase (UNAG), albumin (UALB), kidney injury molecule-1 (UKim-1), and cadmium. The associations among urinary cadmium, plasma TGF-β1/Smad3, and kidney injury were analyzed. The expressions of miRNAs between cadmium exposure with kidney damage group and control group were compared by 1:1 matched casecontrol design.
Results The urinary cadmium level of the exposed group (1.06 μg/g, adjusted by urinary creatinine, thereafter) was higher than that of the control group (0.74 μg/g) (P < 0.001). Compared with the control group, the levels of plasma TGF-β1, plasma Smad3, UNAG, and UALB were significantly higher in the exposed group (P < 0.05). With the increasing of age, the levels of UNAG and UALB in the exposed group and the levels of UNAG and UKim-1 in the control group increased significantly (Ptrend < 0.01). The Pearson correlation analysis results showed that plasma TGF-β1 had a positive correlation with UNAG and plasma Smad3 (r=0.133, P < 0.001; r=0.091, P < 0.05). The regression analysis results showed that urinary cadmium was closely associated with UNAG (b=0.285, 95% CI:0.076-0.494), UALB (b=0.738, 95% CI:0.385-1.092), and UKim-1 (b=0.038, 95% CI:0.014-0.062). The expression levels of miRNA-21, miRNA-192, and miRNA-126 were higher in the cadmium exposure and kidney damage group than those of the control group.
Conclusion The levels of peripheral blood TGF-β1 and Smad3 are increased among the participants with low-level environmental exposure to cadmium. The increasing expression levels of miRNA-21, miRNA-192, and miRNA-126 might be involved in the renal impairment associated with cadmium exposure.
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