氧自由基在急性镉中毒性肾损伤中的作用

目的探讨氧自由基在急性镉中毒性肾损伤中的作用。方法给大鼠腹腔注射ＣｄＣｌ２（１５μｍｏｌ／ｋｇ）与巯基乙醇（３００μｍｏｌ／ｋｇ）混合液制备急性镉中毒性肾损伤模型，观察染镉后不同时间肾细胞线粒体、胞浆中一系列脂质过氧化指标的变化，同时测定肾皮质镉含量，检测肾功能和肾脏超微结构的改变。结果染镉后２小时肾皮质镉含量已达峰值；超微结构出现改变；氧自由基生成及丙二醛（ＭＤＡ）含量亦显著高于对照组（Ｐ＜０．０１），超氧化物歧化酶（ＳＯＤ）、谷胱甘肽过氧化物酶（ＧＳＨ－Ｐｘ）活力下降。至染镉后１２小时，氧自由基产生及脂质过氧化反应达到高峰；肾功能损害亦十分明显；线粒体、溶酶体等细胞器严重受损。结论氧自由基大量生成及由此引起的脂质过氧化反应可能在镉对肾组织的损害中起重要作用。     

锌对急生镉中毒性肾损伤保护作用的研究

目的 研究锌对急性镉中毒性肾损伤的保护作用。方法 给大鼠腹腔注射与巯基乙醇混合染毒液的同时,皮下注射锌。结果 加锌能明显降低肾皮质镉含量,同时亦使肾线粒体,胞浆中铁含量下降,锌含量升高,燕可使染镉后２小时本应增加的脂质过氧化反应有所抑制,但在４小时后作用消失,使ＳＯＤ活性显著升高;但对肾功能及超微结构的改善则不明显。     

镉性肾损伤时肾皮质细胞中微量元素与脂质过氧化改变

目的探讨镉中毒性肾损伤的机制。方法用ＣｄＣｌ２与巯基乙醇的混合液给予Ｗｉｓｔａｒ大鼠一次腹腔注射染毒，制备镉中毒性肾损伤的动物模型，并投用微量元素硒，观察大鼠染毒及给硒后的肾细胞内的微量元素分布及脂质过氧化水平的变化。结果染镉后，大鼠肾细胞线粒体、胞液内硒含量、抗氧化酶活力明显降低，而氧自由基与丙二醛（ＭＤＡ）水平升高；某些必需微量元素在细胞内的分布出现异常。结论加硒可使被镉降低的谷胱甘肽过氧化物酶（ＧＳＨ－Ｐｘ）活力恢复至正常水平，增强的脂质过氧化反应受抑制，受损的肾功能及超微结构得到明显改善。     

总镉和非蛋白结合镉致大鼠肾脂质过氧化作用的研究

目的：探讨非蛋白结合镉，总镉致肾脂质过氧化的作用。方法 利用染镉动物攻凝胶渗透层析技术，观察非蛋白结合镉，总镉在肾脂质过氧化时的作用。结果 镉染毒组谷胱甘肽过氧化物酶（GSH－Px)，超氧化物歧化酶（SOD）活性逐渐下降，谷胱甘肽（GSH），丙二醛（MDA）含量逐渐增加，总镉，非蛋白结合镉与肾GSH之间存在着明显的正相关关系（r分别为0.898,0.751) ,与肾SOD之间存在着明显的负相关关系（r分别为-0.896,-0.767)，此外总镉还与肾GSH－Px存在着明显的负相关关系（r=-0.756)。结论 总镉，非蛋白结合镉均能引起肾脂质过氧化，但总镉比非蛋白结合镉可能具有更重要的意义。而有关肾GSH升高的机制有待进一步研究。     

锌对急性镉中毒性肾损伤保护作用的研究

目的研究锌对急性镉中毒性肾损伤的保护作用。方法给大鼠腹腔注射ＣｄＣｌ２（１５μｍｏｌ／ｋｇ）与巯基乙醇（３００μｍｏｌ／ｋｇ,ｍｅｒｃａｐｔｏｅｔｈａｎｏｌ,ＭＥ）混合染毒液的同时,皮下注射锌（ＺｎＳＯ４１５μｍｏｌ／ｋｇ）。结果加锌能明显降低肾皮质镉含量,同时亦使肾线粒体、胞浆中铁含量下降,锌含量升高,并可使染镉后２小时本应增加的脂质过氧化反应有所抑制,但在４小时后作用消失,使ＳＯＤ活性显著升高;但对肾功能及超微结构的改善则不明显。结论氧自由基损伤可能是镉中毒性肾损伤的主要机制,锌对镉中毒性肾损伤的拮抗作用不明显,是否与剂量等因素有关,尚待进一步研究。     

锌金属硫蛋白对镉致肝肾损伤的修复作用研究

目的：探讨锌金属硫蛋白（Zn-MT）对镉所导致的肝肾毒性的修复作用。方法：以小鼠为研究对象，建立镉中毒动物模型，然后经口给予不同剂量的Zn-MT,测定并分析肝、肾组织中脂质过氧化代谢产物丙二醛（MDA）水平、超氧化物歧化酶（SOD）、谷胱甘肽过氧化酶（GSH－Px）活性及电镜下观察肝肾组织形态学变化。结果：Zn-MT可明显降低肝、肾组织中MDA水平，使肝、肾组织中SOD、GSH－Px活力有一定程度的恢复，且上述作用呈明显的剂量－反应关系；电镜下观察到给予Zn-MT后，肝、肾组织形态学病变得到一定程度的恢复。结论：Zn-MT可对镉所致的肝肾组织脂质过氧化损伤起到一定的修复作用。     

强化SOD刺梨汁治疗镉中毒大鼠

目的研究强化超氧化物歧化酶（ＳＯＤ）刺梨汁对镉中毒大鼠的治疗作用，并初步探讨其作用机制。方法给大鼠染镉同时口服强化ＳＯＤ刺梨汁，测定其尿、血、组织镉含量和ＳＯＤ、丙二醛（ＭＤＡ）、肾功能。结果刺梨汁可促进染镉大鼠２４小时尿镉的排泄，降低其血及肝、肾镉含量，增加其血及组织中ＳＯＤ活力，减少脂质过氧化产物ＭＤＡ生成，作用明显强于ＶｉｔＣ。结论刺梨汁不但有驱镉作用，且能拮抗自由基、脂质过氧化的损害和保护肾功能。刺梨汁对中毒的治疗作用可能与其富含ＳＯＤ、ＶｉｔＣ、ＶｉｔＥ、刺梨多糖及硒、锌等成分有关。     

硒对急性镉中毒性肾损伤保护作用的研究

研究硒对急性镉中毒性肾损伤的保护作用。给大鼠腹腔注射镉（ＣｄＣｌ２１５μｍｏｌ／ｋｇ）与巯基乙醇（ｍｅｒｃａｐｔｏｅｔｈａｌ，ＭＥ３００μｍｏｌ／ｋｇ）混合液的同时，皮下注射硒（Ｎａ２ＳｅＯ３１５μｍｏｌ／ｋｇ）。结果显示：加硒能明显降低肾皮质镉含量，降低肾线粒体、胞浆氧自由基含量，并可拮抗镉所致大鼠线粒体的脂质过氧化物含量，使ＧＳＨ－Ｐｘ活性在１２小时后显著升高；同时使镉所致肾功能及超微结构损伤得到改善。提示硒可能通过抗氧化作用来防治镉所致肾损伤。     

新型络合剂对肾镉促排作用及对微量元素影响的观察

为观察新型络合剂Ｇ－Ｃｙｓ－ＤＴＣ、Ｇ－Ｔｈｒ－ＤＴＣ对染毒大鼠肾内蓄积镉的络合促排作用及对肾皮质元素分布的影响，比较促排治疗对肾皮质铁、铜、锌等含量的影响，利用北京正负电子对撞机提供的硬Ｘ射线对肾皮质冰冻切片扫描及原子吸收分光光度法、Ｘ射线荧光测定染毒鼠肾皮质镉及其他元素含量。结果，新型络合剂Ｇ－Ｃｙｓ－ＤＴＣ、Ｇ－Ｔｈｒ－ＤＴＣ能大幅度降低肾内镉负荷。染毒肾皮质中Ｃｄ与Ｓｅ密切相关，而Ｚｎ和Ｓｅ的相关性下降。提示新型络合剂对肾内蓄积镉有较好驱排效果；硒和锌在镉中毒作用机制中可能起一定的保护作用。     

镉中毒时肾细胞内微量元素含量的改变

目的了解微量元素在镉中毒性肾损伤中的作用及机制。方法制备镉中毒性肾损伤的动物模型，测定了肾细胞亚细胞成分中微量元素的含量、脂质过氧化反应及肾功能、超微结构的改变。结果镉的摄入使主要分布于线粒体的铜、锌、锰向胞核和胞浆转移，而线粒体、胞液中硒含量与谷胱甘肽过氧化物酶活性均降低，丙二醛则升高。结论提示镉性肾损伤时微量元素尤其是硒的改变可能与脂质过氧化反应增强有关，细胞内微量元素分布异常也可能是影响镉性肾损伤的重要因素之一。     

Renal effects of cadmium exposure in cadmium nonpolluted areas in Japan

Long-term exposure to cadmium (Cd) causes renal damage in the general population. The maximum allowable urinary Cd concentration, which was calculated from our previous study performed in a Cd-polluted area, was almost the same as the mean urinary Cd concentration of people living in nonpolluted areas. We assessed whether environmental Cd exposure is related to renal dysfunction of people in nonpolluted areas in Japan. Blood and urine samples were collected from 2753 subjects (1105 men and 1648 women) ages over 50 years old in three nonpolluted areas. Blood was analyzed for Cd and urine was analyzed for Cd, total protein, beta(2)-microglobulin (beta(2)-mg), and N-acetyl-beta-D-glucosaminidase (NAG). Cd in blood or urine was employed as indicators of internal dose; and urinary total protein, beta(2)-mg, and NAG were used as an indicator of renal dysfunction. Multiple regression analysis and logistic regression analysis were performed to clarify the dose-effect and dose-response relationship between blood or urinary Cd concentration and indicators of renal dysfunction. Multiple regression analysis demonstrated a significant dose-effect relationship between Cd in blood and urine and indicators of renal dysfunction. Logistic regression analysis also showed that the probability that individual subjects would have abnormal values of the renal variables was significantly related to Cd in blood and urine.     

Ⅱ型糖尿病小鼠对镉金属硫蛋白致肾脏毒性的易感性

[目的]探讨Ⅱ型糖尿病小鼠对重复性镉金属硫蛋白（CdMT)染毒致肾脏损伤的易感性。[方法]18只6月龄雄性Ⅱ型糖尿病小鼠（Umea ob/ob小鼠）和18只同种系非Ⅱ型糖尿病的雌性瘦型小鼠（正常小鼠）,各自随机分为3个组,采用背部皮下注射方式染毒。为了使两种类型小鼠肾皮质中达到相似的染镉浓度,根据两种小鼠肾脏体系数之比值来确定不同的CdMT染毒剂量。[结果]ob/ob小鼠尿NAG、尿钙及肾皮质钙含量在低肾皮质镉剂量时升高,而瘦型小鼠在试剂量时的相应指标无明显改变。[结论]本研究提示Ⅱ型糖尿病小鼠对镉的肾脏毒性易感。     

铅中毒肾损害早期检测的实验研究

雄性大鼠腹腔注射醋酸铅5mg/kg 体重,5次/周、连续12周,肾脏出现明显的形态和功能异常。尿r-GT 活性降低是最早出现的改变,其阳性检出率也较尿蛋白、尿糖为高。表明尿r-GT 作为铅中毒肾损害的早期检测指标有一定价值,但对其特异性有待进一步研究。     

Significance of the excretion of urinary indicator proteins for a low level of occupational exposure to cadmium

Urinary cadmium (Cd), N-acetyl-beta-D-glucosaminidase (NAG), metallothionein (MT), beta 2-microglobulin (BMG), and blood cadmium were determined in 79 workers who had been employed at a Cd pigment factory in Japan. The workers who had been dealing with Cd pigment manufacturing processes were estimated to be exposed to cadmium pigment dust at a maximum concentration of 3.0 micrograms/m3/8 h for about 20 years. The urinary Cd level ranged from 0.2 to 9.7 micrograms/g creatinine with a geometric mean of 1.02 micrograms/g creatinine. Pearson's correlation coefficients between logarithm of urinary Cd and that of NAG, MT, and BMG in urine were 0.45, 0.62, and 0.05, respectively. The correlation coefficients between blood Cd and urinary NAG, MT, and BMG were 0.21, 0.40, and -0.074, respectively. When partial correlation coefficients were calculated to exclude the contribution of age factor, urinary Cd turned out to be significantly correlated with urinary MT (r = 0.55) and NAG (r = 0.52). The present results indicate that urinary Cd is more closely associated with urinary MT and NAG than with BMG, and suggest that MT and NAG could be good indicators of Cd absorption in a Cd-exposed population whose mean urinary Cd level is relatively low, or less than 10 micrograms/g creatinine.     

Assessment of urinary protein 1 and transferrin as early markers of cadmium nephrotoxicity.

Transferrin and protein 1, a sex linked alpha 2-microprotein, were assayed in urine from 58 workers exposed to cadmium (Cd) in a non-ferrous smelter and from 58 age matched referents. These two new markers of nephrotoxicity were compared with urinary beta 2-microglobulin (beta 2-m), retinol binding protein (RBP), albumin, and beta-N-acetyl-glucosaminidase (NAG). The response of protein 1 to Cd tubulotoxicity was similar to that of beta 2-m, RBP, and NAG. In Cd workers, protein 1 had a correlation with urinary Cd (r = 0.56) similar to beta 2-m (r = 0.48), RBP (r = 0.58), and NAG (r = 0.49). Values of these three low molecular weight proteins and of NAG were increased only in workers with urinary Cd higher than 10 micrograms/g creatinine. Urinary transferrin and albumin were similarly affected by exposure to Cd. Their response, however, was clearly more sensitive than that of low molecular weight proteins. Prevalences of positive values of these two high molecular weight proteins were not only higher but also tended to rise at lower concentrations of Cd in urine or blood. This finding suggests that in some subjects subtle defects in glomerular barrier function may precede the onset of proximal tubular impairment after chronic exposure to Cd. It remains to be assessed whether these subjects are more at risk of developing renal insufficiency.     

Assessment of urinary protein 1 and transferrin as early markers of cadmium nephrotoxicity

Transferrin and protein 1, a sex linked alpha 2-microprotein, were assayed in urine from 58 workers exposed to cadmium (Cd) in a non-ferrous smelter and from 58 age matched referents. These two new markers of nephrotoxicity were compared with urinary beta 2-microglobulin (beta 2-m), retinol binding protein (RBP), albumin, and beta-N-acetyl-glucosaminidase (NAG). The response of protein 1 to Cd tubulotoxicity was similar to that of beta 2-m, RBP, and NAG. In Cd workers, protein 1 had a correlation with urinary Cd (r = 0.56) similar to beta 2-m (r = 0.48), RBP (r = 0.58), and NAG (r = 0.49). Values of these three low molecular weight proteins and of NAG were increased only in workers with urinary Cd higher than 10 micrograms/g creatinine. Urinary transferrin and albumin were similarly affected by exposure to Cd. Their response, however, was clearly more sensitive than that of low molecular weight proteins. Prevalences of positive values of these two high molecular weight proteins were not only higher but also tended to rise at lower concentrations of Cd in urine or blood. This finding suggests that in some subjects subtle defects in glomerular barrier function may precede the onset of proximal tubular impairment after chronic exposure to Cd. It remains to be assessed whether these subjects are more at risk of developing renal insufficiency.     

On the proposed role of metallothionein in the transport of cadmium

In order to test a possible role of MT in the transport of Cd from liver to kidney, we compared the distribution of ¹⁰⁹Cd administered either in the form of CdCl₂ or CdMT. Unlike in earlier studies which employed relatively massive amounts of Cd, in the present studies a low total amount of Cd (15–30 μg) was continuously infused over a period of 2–3 days. Results confirmed a preferential renal accumulation of CdMT. High intracellular renal and hepatic MT concentrations, induced by repeated prior injections of Cd, Zn, or Hg, did not alter the tissue distribution of infused CdCl₂ or CdMT. It is interesting to note that in some further experiments, equivalent amounts of extracellular MT depressed renal uptake of CdMT. These findings are consistent with a role of MT in the transport of Cd from liver to kidney.     

A nine year follow up study of renal effects in workers exposed to cadmium in a zinc ore refinery.

Renal changes with time have been studied in 14 workers engaged in the production of cadmium (Cd) in a zinc ore refinery. These workers were examined once a year in the period 1980 to 1985 and 13 of them also in 1989. Four of the workers (group A) had been employed in an old Cd plant before 1973 and had received higher exposures to Cd than the other workers (group B). Average urinary Cd concentrations over the whole study period in workers of group A ranged from 6.9 to 9.2 micrograms/g creatinine (median 8.4 micrograms/g) and in workers of group B from 0.64 to 7.1 micrograms/g creatinine (median 1.9 micrograms/g). Renal effects were assessed by the determination of urinary N-acetyl-beta-D-glucosaminidase (NAG), beta 2-microglobulin (beta 2-M), retinol binding protein, albumin, total protein, and serum creatinine concentrations and activity. Urinary beta 2-M concentrations in three of four workers of group A were close to or marginally above the upper normal limit during the study period. The beta 2-microglobinuria was not, however, progressive. No values outside normal limits were detected for any of the other renal tests in workers of groups A and B, related to exposure to Cd. Dose-response relations showed that urinary Cd correlated significantly with urinary NAG activity and total protein and beta 2-M. The earliest change induced by Cd was seen for urinary NAG activity within normal limits of NAG excretion. The regression lines were similar in the surveys between 1981 and 1989, indicative of no progression to higher values for any of the renal tests. The current biological exposure index (BEI) of 10 micrograms/g creatinine for workers exposed to Cd, set by the American Conference of Governmental Industrial Hygienists (ACGIH), therefore seems justified, although the safety margin is small. The World Health Organisation recommended limit and ACGIH (1992-3) proposed limit of 5 micrograms/g creatinine would provide a much larger safety margin, and could be regarded as an action point for increased health surveillance.     

Renal function after reduction in cadmium exposure: an 8-year follow-up of residents in cadmium-polluted areas

Background and objective: Long-term exposure to cadmium (Cd) causes renal dysfunction, but the change in renal function with exposure is unknown. We assessed the evolution of Cd-induced renal effects after a reduction in dietary exposure to Cd in rice.Methods: Four hundred twelve residents in previously Cd-polluted and nonpolluted areas were examined twice, in 1998 and in 2006. Changes in blood Cd, urinary Cd, and kidney function [N-acetyl-β-d-glucosaminidase (NAG), β₂-microglobulin, and albumin in urine] were measured.Results: In the most polluted area, mean blood Cd was 8.9 μg/L and 3.3 μg/L in 1998 and in 2006, respectively, and urinary Cd was 11.6 and 9.0 μg/g creatinine. Urinary albumin in 1998 increased with urinary Cd, but no such exposure–response relation appeared for 2006 albumin versus urinary Cd 1998, indicating recovery. Other biomarkers of kidney function were also elevated in 1998. Partial recovery was observed for NAG among women and was suggested for β₂-microglobulin among young individuals. The probability of having β₂-microglobulin levels above the 95th percentile in 2006 was high in those with elevated β₂-microglobulin in 1998 [odds ratio (OR) = 24.8; 95% confidence interval (CI): 11.2, 55.3] compared with albumin (OR = 3.0; 95% CI: 1.2, 7.5) and NAG (OR = 2.6; 95% CI: 1.6, 4.4).Conclusions: Results suggest that a Cd-mediated increase in urinary albumin excretion is reversible upon substantial reduction of exposure. For markers of tubular effects, we observed a tendency toward improvement but not complete recovery. Data from repeated observations suggest that β₂-microglobulin may be more informative than NAG as an indicator for an individual’s future tubular function.     

异搏定和氯丙嗪对镉慢性肾毒性影响的实验研究

目的:对慢性镉染毒(Cd)大鼠投予异搏定(Ver)和氯丙嗪(CPZ),探讨这两种物质对镉慢性肾损伤的影响。方法:实验用4组大鼠,单纯镉染毒组和Ver、CPZ预处理组均皮下注射含Cd 1．4mg／kg的氯化镉(CdCl2)溶液,每周3次,连续6周。Ver和CPZ预处理组在每次皮下注射CdCl2前1h,分别向腹腔注射Ver 4mg／kg和CPZ 5mg／kg,,对照组大鼠在相同时间注射生理盐水5ml／kg,,在实验开始后第2,4,6周时收集尿样,测定尿N-乙酰-B—D-氨基葡萄糖苷酶(NAG)活力和尿蛋白含量。最后一次注射后24h处死大鼠,采集血液,取肾脏,测定血清尿素氮(BUN),血、肾皮质和尿中的Cd、Ca及血、肾皮质中丙二醛(MDA)含量。结果镉染毒4周时,与单纯镉染毒组比较,Ver和CPZ预处理组的尿NAG活力和尿蛋白含量均明显降低;镉染毒6周时,Ver和CPZ预处理组的血Cd、血清BUN、尿Ca及肾皮质MDA含量均明显降低。CPZ预处理组肾皮质Cd和血MDA含量也明显降低。结论:Ver和CPZ具有防止镉所致慢性肾损伤的作用,其机制可能是减轻镉对肾脏的脂质过氧化损伤。