Changes in the structure and function of the kidney of rats chronically exposed to cadmium.: I.: Biochemical and histopathological studies
Changes in the structure and function of the kidney of rats chronically exposed to cadmium.: I.: Biochemical and histopathological studies
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DOI：
10.1007/s00204-003-0451-1
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发表时间：
2003-06-01
影响因子：
6.1
通讯作者：
Moniuszko-Jakoniuk, J
中科院分区：
文献类型：
--
作者：
Brzóska, MM;Kaminski, M;Moniuszko-Jakoniuk, J
本研究的目的是评估慢性暴露于镉（Cd）对肾脏结构和功能的影响，以及建立镉的身体负担的变化发生。为此目的，我们已经创建了一个实验模型，使用大鼠中毒镉在饮用水中的浓度为5或50毫克镉/升的6，12和24周。肾损害程度进行了评价生化和组织病理学。使用镉诱导的近端肾小管损伤的敏感生物标志物，如尿总N-乙酰-β-D-氨基葡萄糖苷酶（NAG-T）及其同工酶B（NAG-B）和碱性磷酸酶（ALP）。肾脏中的镉含量随着暴露水平和持续时间的增加而增加，导致剂量和时间依赖性的结构性和功能性肾衰竭。在大鼠暴露于5毫克镉/升，第一个症状的损伤的主要小管的长和短的肾单位（上皮细胞的结构损伤，增加尿NAG-T和NAG-B的活动）后，注意到12周的实验。损害发生在低肾镉浓度达4.08 +/- 0.33微克/克湿重（平均标准误）和尿浓度为4.31 +/- 0.28微克/克肌酐。暴露于50 mg Cd/l时，6周后已明显出现肾小管损伤（肾小管上皮结构模糊、刷状缘萎缩、细胞部分碎裂并将细胞核释放到管腔中以及NAG-T、NAG-B和ALP的尿活性增加），肾脏Cd浓度为24.09 +/- 1.72 mug/g湿重。在大鼠暴露于50毫克镉/升，缺乏规则的肾小球轮廓后，注意到12周，而24周后毛细血管增厚和扩大的过滤空间是明显的。暴露于镉24周后，血清中尿素浓度增加，同时尿液中尿素水平降低，表明尿素清除率降低，总蛋白排泄增加，但内生肌酐清除率不受影响。在较低的暴露量下，在实验24周后，肾小球的结构性而非功能性损伤的症状也很明显。我们的研究结果提供的证据表明，慢性暴露于镉剂量依赖性损害（结构和功能）的整个肾脏。损伤影响肾单位的主要吸收部分（近曲小管和直小管）和过滤部分（肾小球）。但镉作用的靶点是主小管。我们假设镉对肾脏影响的阈值小于4.08 +/- 0.33 mug/g湿肾重，大于2.40 +/- 0.15 mug/g（在此镉浓度下，未观察到肾损伤症状），并且可能接近后一值。这项研究的一个非常重要的发现是，镉作用于整个肾脏，特别是对主肾小管，即使在这个器官中的相对较低的积累。它证实了这一假设，即人类环境暴露于镉，特别是吸烟者，在肾小管功能障碍的风险。
The aim of this study was to assess the effects of chronic exposure to cadmium (Cd) on the structure and function of kidneys, as well as to establish the body burden of Cd at which the changes occur. For this purpose we have created an experimental model using rats intoxicated with Cd administered in drinking water at the concentration of 5 or 50 mg Cd/l for 6, 12 and 24 weeks. The degree of kidney damage was evaluated biochemically and histopathologically. Sensitive biomarkers of Cd-induced proximal tubular injury such as urinary total N-acetyl-beta-D-glucosaminidase (NAG-T) and its isoenzyme B (NAG-B), and alkaline phosphatase (ALP) were used. Cd content in the kidney increased with the level and duration of exposure leading to dose- and time-dependent structural and functional renal failure. In rats exposed to 5 mg Cd/l, first symptoms of injury of the main tubules of long and short nephrons (structural damage to epithelial cells, increased urinary activities of NAG-T and NAG-B) were noted after 12 weeks of the experiment. The damage occurred at a low kidney Cd concentration amounting to 4.08 +/- 0.33 mug/g wet weight (mean SE) and a urinary concentration of 4.31 +/- 0.28 mug/g creatinine. On exposure to 50 mg Cd/l, damage to the main tubules (blurred structure of tubular epithelium, atrophy of brush border, partial fragmentation of cells with release of nuclei into tubular lumen as well as increased urinary activities of NAG-T, NAG-B and ALP) was already evident after 6 weeks with the kidney Cd concentration of 24.09 +/- 1.72 mug/g wet weight. In rats exposed to 50 mg Cd/l, a lack of regular contour of glomeruli was noted after 12 weeks, whereas after 24 weeks thickening of capillary vessels and widening of filtering space were evident. After 24 weeks of exposure to Cd, increased urea concentration in the serum with simultaneous decrease in its level in the urine, indicating decreased clearance of urea, and increased excretion of total protein were observed, but endogenous creatinine clearance remained unaffected. At the lower exposure, symptoms of structural, but not functional, damage to the glomeruli were also evident after 24 weeks of the experiment. Our results provide evidence that chronic exposure to Cd dose-dependently damages (structurally and functionally) the whole kidney. The injury affects the main resorptive part (proximal convoluted tubules and straight tubules) and the filtering part (glomeruli) of the nephron. But the target site for Cd action is the main tubule. We hypothesize that the threshold for Cd effects on the kidney is less than 4.08 +/- 0.33 mug/g wet kidney weight and greater than 2.40 +/- 0.15 mug/g (at this Cd concentration no symptoms of kidney damage were noted), and it may be close to the latter value. A very important finding of this study is that Cd acts on the whole kidney, especially on the main tubules, even at relatively low accumulation in this organ. It confirms the hypothesis that humans environmentally exposed to Cd, especially smokers, are at risk of tubular dysfunction.