Copper In Kidney Research Articles

Iron, zinc, and copper levels in different tissues of clinically vitamin A-deficient rats

To clarify the effect of vitamin A deficiency on iron, zinc, and copper status in different tissues, three groups of rats were fed two types of synthetic diets for 52 d. Group one, which was fed a vitamin A-deficient diet, showed severe signs of vitamin A deficiency. Groups two (fed restricted amount, pair-fed with group one), and three (fed diet ad libitum) were fed a control diet. After said period of feeding, iron, zinc, and copper were measured in different tissues. Significant changes observed when the groups were compared are summarized below: 1. Iron and copper in testes were increased significantly, whereas zinc was strikingly decreased in group one when compared with the other groups; 2. Copper (in lung and kidney) and iron (in the spleen) were increased significantly in group one compared with the other groups; 3. In the liver, iron, zinc, and copper were significantly different between group one and group two; 4. In muscle, iron was significantly higher in group one than group two; 5. In tibia and blood, iron levels (but not zinc and copper) in groups one and two were significantly higher than group three. These results suggest that vitamin A deficiency affects iron, zinc, and copper status in rats.

Effects of chronic copper exposure on the macrophage chemiluminescent response and gill histology in goldfish (Carassius auratusL.)

The effects of chronic copper exposure on the macrophage chemiluminescent response and gill histology in goldfish (Carassius auratusL.) were determined. Fish were exposed to sublethal concentrations (30, 65, 100, and 175ppb) of copper sulphate for 96h. Pronephric (head kidney) cells were collected and were comprised on lymphocytes, thrombocytes, monocytes/macrophages neutrophils and eosinophils/basophils (cell types grouped due to difficulty in identification). There were no significant differences in population profiles of cells used for chemiluminescence studies after exposure to 100ppb copper. Density gradient-separated cells were stimulated with zymosan, the luminol-enhanced chemiluminescence (CL) response was measured and the results were compared to non-copper exposed controls. There was a significant correlation between copper concentration and reduction in the time at which the peak CL response [time to peak (TTP) CL] occurred. In addition, there was a significant parabolic dose response curve for peak CL response, which suggests increased production of reactive oxygen intermediates by phagocytes from fish exposed to concentrations up to 100ppb, followed by inhibition at 175ppb. These results indicate that copper affects phagocyte function in a complex manner, stimulating or inhibiting production of reactive oxygen intermediates depending on copper concentration. Exposure to concentrations of copper also resulted in varying degrees of gill hyperplasia. The relative median severity score (a score assigned to each gill based upon the amount of hyperplasia seen in a histological section) correlated significantly with the copper concentration. In addition, there was a very high correlation between the degree of hyperplasia and the TTP CL response. Levels of copper in the head kidney of goldfish exposed to 100ppb were similar to controls as measured by atomic absorption spectroscopy. Thus, changes in the CL response of head kidney phagocytes of fish exposed to copper may be caused indirectly, via effects on other immunoregulatory cells or other physiological mechanisms. We conclude that addition of heavy metals such as copper to water can modify the CL responses of phagocytes and alter the histopathology of the gills inC. auratus.

Copper metabolism in analbuminaemic rats fed a high-copper diet

Copper metabolism in male Nagase analbuminaemic (NA) rats was compared with that in male Sprague Dawley (SD) rats fed purified diets containing either 5 or 100 mg Cu/kg diet. Dietary copper loading increased hepatic and kidney copper concentrations in both strains to the same extent, but baseline values were higher in the NA rats. There was no strain difference in true and apparent copper absorption nor in faecal endogenous and urinary copper excretion. NA rats had higher levels of radioactivity in kidneys at 2 hr after intraperitoneal administration of 64Cu. As based on the distribution of added 64Cu, about 70% of plasma copper appeared to be in the non-protein compartment in the NA rats, whereas in SD rats, it was only about 1%. It is concluded that the NA rats are able to maintain a relatively normal metabolism of copper, even after dietary copper challenge. In the NA rats, zinc concentrations in kidneys, liver and urinary zinc excretion were elevated when compared with SD rats. The high-copper diet did not affect tissue zinc concentrations and apparent zinc absorption in both strains of rats.

Inorganic mercury exposure, mercury-copper interaction, and DMPS treatment in rats.

The aim of this study was to evaluate the efficiency of oral treatment with sodium 2,3-dimercaptopropane-1-sulfonate (DMPS) on reducing mercury deposits in rat kidney after chronic exposure to inorganic mercury. The effect on kidney copper levels was also evaluated. The results showed that after two months of exposure to 50 ppm of mercury (as mercuric chloride) the concentration of mercury in the kidney was 124 micrograms/g wet tissue. At the same time copper concentration rose from 11 to 77 micrograms/g. DMPS treatment caused 2- and almost 4-fold reduction of mercury and copper, respectively. This study demonstrates that chronic exposure to inorganic mercury may alter metabolism of copper and that DMPS is an effective means for reduction of both mercury and copper.

Levels of cadmium, zinc and copper in renal cell carcinoma and normal kidney.

Levels (microgram/g dry weight) of cadmium (Cd), zinc (Zn) and copper (Cu) were determined in kidneys with renal cell carcinoma from 20 male and 11 female patients. Autopsied kidneys from nine males and eight females who had died of nonmalignant diseases were used as controls. The mean levels in cortex of Cd was in cases 103.2 and in controls 79.9 (not significantly different). For non-smoking cases, mean level of Cd in cortex was somewhat lower than in the controls. No significant differences were found between cases and controls for Cd levels in the medulla. Zn in cortex was significantly lower in the cases aged > or = 69 years (mean 182.0) than in the corresponding controls (mean 237.6). Zn in medulla was significantly lower in all cases (mean 103.5) than in controls (mean 162.2). The mean level of Cu in the medulla in cases was 10.7 and in controls 13.0 (P = 0.05). No differences were found for Cu levels in cortex.

Quantitative immunohistochemical evaluation by image analysis of metallothionein in copper-loaded rat kidney.

Kidneys of copper-loaded rats were investigated immunohistochemically with a directly peroxidase-conjugated monoclonal antibody against metallothionein (MT). By means of an image analyzing system the area and the staining intensity of MT immunoreactivity in the proximal convoluted tubule (PCT) cells were determined. In the present study we compared the data obtained by image analysis with analytically determined tissue copper and MT concentrations of rats fed a high-copper diet (1 g/kg) for 16 weeks and sacrificed sequentially during this period. Our results provide evidence that the area of MT immunoreactivity correlates significantly with tissue copper and MT concentrations. Both the copper and MT concentrations in kidney rose to a maximum at 8 weeks and remained constant thereafter. The observed rise in the staining intensity of MT in PCT cells to a maximum at 6 weeks, which subsequently declined, suggests a continuing redistribution of copper and MT in the kidneys even after a maximum of concentration copper and MT is reached in the tissue.

Kidney trace metal response to combined cisplatin (CDDP) and hyperthermia.

The effects of hyperthermia (HY) on cisplatin (CDDP) nephrotoxicity and kidney metal concentrations were evaluated in female F344 rats. Rats were anaesthetized with a xylazine/ketamine mixture, heated on a water-bed for 1 h to an intraperitoneal temperature of 41.1 +/- 0.2 degrees C, and maintained at hyperthermia for an additional 30 min (HY plateau). CDDP (5 mg/kg body weight) was administered at the start of the heating or at the HY plateau. Neither HY alone nor CDDP (5 mg/kg) at normothermia produced a significant effect on weight loss or nephrotoxicity. CDDP administered at the start of heating produced a moderate 1.5-fold increase in serum urea nitrogen (SUN) and serum creatinine concentrations. CDDP administered at the HY plateau produced a significant six-fold increase in SUN and a four-fold increase in creatinine concentration. Weight loss increased two- to three-fold from the combined regimen, but only the rats given CDDP at the HY plateau continued to lose weight through day 7. A loss of kidney copper (50-60%) resulted from the combined regimen, similar to losses observed with higher doses of CDDP at normothermia. HY alone had little effect on concentrations of kidney copper or zinc up to 4 days post-treatment. The results demonstrate that systemic hyperthermia significantly increases CDDP nephrotoxicity in F344 rats and that kidney copper loss from CDDP exposure at hyperthermia is similar to the loss observed from CDDP at normothermia.

Cadmium, zinc, copper, and metallothionein levels in the kidney and liver of inhabitants of Upper Silesia (Poland)

The levels of Cd, Zn, Cu and metallothionein (MT) were determined in renal cortex and liver of 75 subjects decreased in the period 1986-1989 in the area of Upper Silesia (Katowice). The mean age of the population studied was 53.6 +/- 14.6 years. The determined levels (mean +/- SD) were: 43.1 +/- 23.5 micrograms Cd/g; 52.5 +/- 17.4 micrograms Zn/g; 2.2 +/- 0.7 microgram Cu/g; 0.80 +/- 0.36 mumol Hg/g in renal cortex and 3.5 +/- 2.5 micrograms Cd/g; 82.8 +/- 34.3 micrograms Zn/g; 4.5 +/- 2.6 micrograms Cu/g; 0.69 +/- 0.44 mumol Hg/g in the liver. The level of Cd in renal cortex was 40% higher in smokers compared to nonsmokers and was independent of the gender. Whole-body retention of Cd was 34.1 +/- 18.5 mg; smoking elevated the value from 27.1 to 38.2 mg. Compared with a similar study made in central Poland (Lódź), a significant difference was found only regarding the level of Zn and MT in the liver, pointing to the possibility that exposure to this element in the region of Upper Silesia may be higher.

Elevated Intestinal Absorption of Copper in Rats Fed on a Excessive Tyrosine Diet

Recently we reported increased serum levels of copper and of ceruloplasmin activity in rats fed a diet with excess tyrosine. In this study, we found increases in the apparent absorption of copper from the intestines and in the concentrations of kidney copper and metallothionein in rats on the same diet.

Cisplatin-induced loss of kidney copper and nephrotoxicity is ameliorated by single dose diethyldithiocarbamate, but not mesna

Platinum, copper, and zinc concentrations in kidney and liver were monitored following administration of cis-diamminedichloroplatinum (Cisplatin, CDDP) alone or in combination with diethyldithiocarbamate (DDC) or mercaptoethanesulfonate (mesna). Compounds were administered in saline to F344 female rats as single bolus ip doses: 7.5 mg CDDP/kg body wt; 500 mg DDC/kg body wt 1 hr after CDDP; and 100 mg mesna/kg body wt 1 hr before CDDP, at the same time as CDDP, or 1 hr after CDDP. Tissues were collected at 4 hr, 1 day, 4 days, and 7 days post-CDDP dosing. CDDP alone produced significant increases in blood urea nitrogen (fourfold) and plasma creatinine (threefold) concentrations by Day 4. Concurrent with the toxicity, CDDP lowered kidney copper (−71%) by Day 4, but had little effect on liver copper except in copper-pretreated rats. Copperpretreated rats initially had a twofold higher kidney copper concentration and a fourfold higher liver copper concentration, but by Day 4, CDDP lowered copper concentrations in both organs to near the noncopper-treated levels. Platinum in kidney and liver rose 72–100% of peak levels within 4 hr post-CDDP and was relatively stable throughout the 7-day test period. Kidney zinc rose significantly by day 4 only in CDDP-treated rats. DDC protected against the kidney toxicity of CDDP and markedly changed kidney copper loss. Within 4 hr, DDC reduced kidney copper 60% while increasing kidney platinum to the highest concentration of any of the treatments. By Day 4, DDC-treated rats had ≈ 50% lower kidney platinum while copper returned toward control levels. A single dose of mesna did not significantly protect against CDDP nephrotoxicity and had little effect on kidney platinum, copper, or zinc. The patterns of copper loss and toxicity from CDDP alone or with DDC suggest that copper be further evaluated for its role in the mechanism of CDDP cytotoxicity.

Identification of proteins involved in intracellular copper metabolism: Low levels of a ≈ 48-kDa copper-binding protein in the brindled mouse model of Menkes disease

Abstract Little is known about copper metabolism at the cellular level. The brindled mouse is an animal model of Menkes disease which is an inborn error of copper metabolism. Control and brindled mice were used to identify copper-binding proteins with possible roles in normal copper metabolism that are affected by the defect in the brindled mice. When 64Cu-labeled hepatic or renal cytosols from control mice were applied to Mono Q or Superose columns, a approximately 48-kDa protein coeluted with the protein fractions which contained the radiolabeled copper. Large decreases in copper binding were detected in these fractions from the brindled mice. The same column fractions which showed decreased copper binding showed large decreases in the levels of the approximately 48-kDa protein. Decreased copper binding and approximately 48-kDa protein were not simply secondary to the abnormal hepatic and renal copper levels that are found in the brindled mice since although their liver copper levels are low, their kidney copper levels are high. Elevated levels of an approximately 80-kDa heat shock protein were also detected in the hepatic and renal cytosols from the brindled mice. Consistent with expression of the primary defect in both the liver and kidney, the levels of the approximately 48- and approximately 80-kDa proteins were affected similarly in both organs. Irrespective of how the low levels of the approximately 48-kDa protein may be related to the basic defect in the brindled mice, the data are consistent with an important role for the approximately 48-kDa protein in intracellular copper metabolism.

The protective role of metallothionein in copper overload: I. Differential distribution of immunoreactive metallothionein in copper-loaded rat liver and kidney

The cytotoxicity of copper is probably determined by its molecular association and subcellular localisation rather than its concentration within tissues. Metallothionein (MT) is a copper binding protein distributed between the particulate and soluble cellular components. The role of MT in conferring protection to the copper-loaded rat has been investigated by comparing the distribution of the immunoreactive protein between the soluble and particulate fractions of liver and kidney during the development of copper tolerance. Young male Wistar rats were fed a high copper (1 g/kg) diet for 16 weeks and killed sequentially during this period; liver and kidneys were retained. Pellet and supernatant preparations from homogenised, pooled samples of liver and kidney were subjected to chromatographic separation. Copper and zinc were analysed in whole tissue, homogenates and eluant fractions and MT identified likewise using an enzyme-linked immunoassay. Copper accumulated for 5 weeks in the liver falling subsequently accompanied by similar changes in MT content. Kidney copper and MT rose to maximum concentrations at 8 weeks and were maintained thereafter. Substantial differences were apparent in the relative distribution of MT between the two organs. MT was the major, predominantly cytosolic, copper-binding protein in the kidney but in the liver immunoreactive MT was pelleted and present in lower concentration than the high molecular weight cuproproteins. It was concluded that whilst MT plays a role in the detoxification and adaptation of rats to copper-loading the regulatory functions of liver and kidney may differ significantly in this respect.

Manganese, copper, zinc, iron, cadmium, mercury and lead in muscle meat, liver and kidneys of poultry, rabbit and sheep slaughtered in the northern part of Poland, 1987

Manganese, copper, zinc, iron, cadmium, mercury and lead concentrations have been determined in muscle meat, livers and kidneys of ducks, geese, chickens, hens, rabbits and sheep slaughtered in the northern part of Poland in 1987. The mean values obtained related to wet weight for muscle meat, livers and kidneys of animals were: 0.11-0.27, 0.73-3.3 and 0.90-1.9 mg/kg Mn; 0.52-7.3, 3.8-88 and 2.8-15 mg/kg Cu; 5.7-40, 20-45 and 21-30 mg/kg Zn; 10-35, 27-83 and 50-180 mg/kg Fe; less than 5-5, 16-140 and 250-5100 micrograms/kg Cd; less than 1-3, 2-10 and 5-12 micrograms/kg Hg; and less than 10-20, 100-210 and 120-1300 micrograms/kg Pb, respectively. Substantial differences have been found in the mean copper concentration in muscle meat, livers and kidneys, zinc and iron in muscle meat, and cadmium in kidneys, between some of the species examined. The mean and maximum concentrations of mercury and lead found in muscle meat and organs of animals in the present study were low, and only in the case of cadmium were somewhat higher values found in kidneys of rabbit and hen. The results obtained are compared with the literature data on the concentrations of the metals examined in muscle meat, livers and kidneys of poultry, rabbit and sheep in Poland or elsewhere.

Response to acute nickel toxicity in rats as a function of sex

The effects of different nickel chloride doses upon blood and plasma glucose and essential metal homeostasis were studied in male and female rats. A definite sex-dependent response to injections of nickel has been observed for both the increase in plasma and blood glucose levels and the time at which these levels peak. Males showed a fast recovery from the rise in glucose levels and were much less affected by changes in the other parameters studied. In females, an extended rise in glucose levels was observed. All these effects are clearly nickel dose-dependent. Plasma, liver and kidney copper levels rose significantly in females while only a small decrease was observed in male kidneys. Zinc levels rose in all organs studied but males recovered to basal levels after the study period, whereas females maintained maximum levels at the end of the same period. An increase in urinary excretion of iron was observed. The present results show that the sex differences to acute nickel toxicity can be a helpful way to study metal interaction and discriminate between specific toxicity due to nickel or that induced by the associated hyperglucagonemia.

The effects of age and sex on seven elements in Sprague-Dawley rat organs

This study reports age-related changes in 7 element (iron, copper, zinc, manganese, mercury, cadmium and lead) concentrations in the liver, kidney and brain of male and female Sprague-Dawley rats from 1 to 364 days of age. Atomic absorption spectrometry was used for the measurements. Copper, mercury and cadmium in the male and female kidneys increased from weaning until 127 days of age, as did iron concentrations in the female liver and kidney. After 127 days, especially, the copper concentration in the female kidney and cadmium concentration in the male and female kidney increased further. Consistent and statistically significant (P less than 0.05) sex differences in element concentrations were found for three elements (iron, copper and zinc). Except for the zinc concentration in the liver from 50 to 72 days, iron (in liver and kidney), zinc (in kidney) and copper (in liver, kidney and brain) concentrations in female rats during the adult stage, were all higher than those of male rats. Isolated differences for other elements (manganese, mercury and cadmium) were also found. The data will be helpful when setting up long-term animal investigations of the biological effect of elements.

Effect of latent iron deficiency on the levels of iron, calcium, zinc, copper, manganese, cadmium and lead in liver, kidney and spleen of growing rats

Feeding a marginally low iron content diet (18-20 mg iron/kg diet) to weaned (21-day-old) rats for 8 weeks produced a significant decrease in liver non-heme iron (66%, p less than 0.001) but no change in blood hemoglobin. Total iron contents of liver (56%, p less than 0.01), spleen (20%, p less than 0.05), and kidney (19%, p less than 0.05) were also found to decrease along with increased zinc, copper, calcium, manganese lead and cadmium in various organs. The magnitude of alteration of a metal was different in different organs. However, liver was found to be the most affected organ. Two weeks of rehabilitation with iron-sufficient diet (390 mg iron/kg diet) normalized these altered levels.

Renal iron handling in the nephrotic syndrome

Renal iron handling was characterized in three experimental models of the nephrotic syndrome: puromycin aminonucleoside, adriamycin and nephrotoxic serum. In adriamycin-induced nephrotic syndrome, which has previously been shown to result from alterations in pore size of the filtration barrier, the transferrin leak was most severe with a fractional clearance of 25%, a value identical to albumin. In contrast, in puromycin nephrotic syndrome and nephrotoxic serum nephritis the fractional clearance of transferrin was never greater than 2% and consistently less than the fractional clearance of albumin. The fact that iron/transferrin ratios in urine and serum were frequently different, sometimes higher other times lower, documents that iron and transferrin can be dissociated in tubule fluid and handled differently in regards to tubule uptake. Kidney iron concentration is also increased in both immunological and non-immunological forms of nephrotic syndrome. In the proximal tubule iron is present largely on the luminal aspect of the cell. In contrast, the major deposition of iron occurs in the lysosomes of the distal tubule cells. Kidney iron concentration does not correlate with tubule fluid iron content but can be prevented from increasing by systemic iron and/or transferrin depletion. This suggests that iron enters the distal tubule cells with transferrin via its receptors from the basolateral side of the distal tubule cells. In association with the increase tubule fluid and kidney iron, there is a marked reduction in kidney selenium and copper content. It is concluded that urinary iron and transferrin losses can vary greatly in different types of experimental renal diseases, and that iron and transferrin can be dissociated in the tubule fluid.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormal movements in brindled mutant mouse heterozygotes: As related to the development of their offspring — Biochemical and morphological studies

As a possible preventive measure for brain dysfunction in Menkes disease, prenatal treatment by maternal administration of zinc, vitamin E and copper was examined in brindled mutant mice. During pregnancy and lactation, female heterozygous mice received 20 ppm zinc or 0.004% alpha-tocopherol acetate (vitamin E) throughout and 6 ppm copper from gestational day 13 in the drinking fluid, ad libitum. The maternal administration of zinc and vitamin E, as antioxidants, or copper resulted in decreased fetal and neonatal death of offspring, especially those of hemizygous males, as compared with the administration of water only. When offspring did not grow, maternal abnormal movements, which comprised rotatory movements of high speed with tremor and ataxia, were frequently observed. In the heterozygotes with abnormal movements, the level of lipid peroxidation in cerebrum and the concentration of copper in kidney were much higher than those in the heterozygotes with normal movement. Morphologically, in cerebellum of the heterozygotes with abnormal movements, the loss of Purkinje cells, abundance of lipofuscin granules and abnormal mitochondria or degenerative bodies of high electron density were frequently observed, as compared with heterozygotes with normal movement. These findings suggest that the development of hemizygous male mice may be influenced by both copper and oxygen radical metabolism.

Chronic copper poisoning in Angora kids

The investigation of five field cases of chronic copper poisoning in a group of 100 Angora kids is reported. Toxicity was confirmed by the demonstration of Heinz body anaemias, necrotizing liver disease, haemoglobinuric nephrosis and excessive levels of copper in blood, livers and kidneys. The dietary history of the kids is described. Tissue levels of copper and reported interactions between selenium, zinc and copper are discussed. Therapeutic and preventative measures are suggested.

Copper, chromium, manganese, nickel and zinc in kidneys of cattle, pigs and sheep and in chicken livers in The Netherlands

Kidneys of cattle, pigs and sheep and chicken livers have been analyzed for contents of copper, chromium, manganese, nickel and zinc. Mean levels found for copper, manganese and zinc correspond well with results of earlier studies as well as with literature data. Contents measured for chromium and nickel are very low: for nickel in porcine kidneys and sheep kidneys median values of 0.045 and 0.022 mg/kg were found. Average contents for nickel in the other tissues and for chromium in all tissues investigated are below 0.01 mg/kg fresh mass. These results for chromium and nickel correspond well with recent results from Sweden, but are lower than most published values.