Changes in the structure and function of the kidney of rats chronically exposed to cadmium. I. Biochemical and histopathological studies.
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 micro g/g wet weight (mean +/-SE) and a urinary concentration of 4.31+/-0.28 micro g/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 micro g/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 micro g/g wet kidney weight and greater than 2.40+/-0.15 micro g/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.
Brzóska
Małgorzata M
MM
Department of Toxicology, Medical University of Białystok, Mickiewicza 2c str., 15-222, Białystok, Poland. mmbr@poczta.onet.pl
Kamiński
Marcin
M
Supernak-Bobko
Dorota
D
Zwierz
Krzysztof
K
Moniuszko-Jakoniuk
Janina
J
D000118:Acetylglucosaminidase / Q000652:urine; D000284:Administration, Oral; D000469:Alkaline Phosphatase / Q000652:urine; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002104:Cadmium / Q000008:administration & dosage* / Q000378:metabolism / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007527:Isoenzymes / Q000652:urine; D007672:Kidney Cortex / Q000737:chemistry / Q000187:drug effects / Q000648:ultrastructure*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000503:physiopathology* / Q000648:ultrastructure*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D007527:Isoenzymes; D002104:Cadmium; D000469:Alkaline Phosphatase; D000118:Acetylglucosaminidase