metallothionein and Kidney-Diseases

The Metallothionein (MT) is a protein which has several interesting biological effects and has been demonstrated increase focus on the role of MT in various biological systems in the past three decades. The studies on the role of MT were limited with few areas like apoptosis and antioxidants in selected organs even fifty years after its discovery. Now acknowledge the exploration of various isoforms of MT such as MT-I, MT-II, MT-III and MT-IV and other isoforms in various biological systems.Strong evidence exists that MT modulates complex diseases and the immune system in the body but the primary function of MT still remains unknown. This review's main objective is to explore the capability to specifically manipulate MT levels in cells and in animals to provide answers regarding how MT could impact those complex disease scenarios.The experimental result mentioned in this review related among MT, zinc, cadmium, diabetic, heart disease, bone retardation, neuro toxicity, kidney dysfunction, cancer, and brain suggest novel method for exploration and contribute significantly to the growing scientist to research further in this field.

Topics: Animals; Bone Diseases, Developmental; Central Nervous System; Diabetes Mellitus; Heart Diseases; Humans; Kidney Diseases; Metallothionein; Neoplasms; Oxidative Stress; Protein Isoforms

The first health effects of cadmium (Cd) were reported already in 1858. Respiratory and gastrointestinal symptoms occurred among persons using Cd-containing polishing agent. The first experimental toxicological studies are from 1919. Bone effects and proteinuria in humans were reported in the 1940's. After World War II, a bone disease with fractures and severe pain, the itai-itai disease, a form of Cd-induced renal osteomalacia, was identified in Japan. Subsequently, the toxicokinetics and toxicodynamics of Cd were described including its binding to the protein metallothionein. International warnings of health risks from Cd-pollution were issued in the 1970's. Reproductive and carcinogenic effects were studied at an early stage, but a quantitative assessment of these effects in humans is still subject to considerable uncertainty. The World Health Organization in its International Program on Chemical Safety, WHO/IPCS (1992) (Cadmium. Environmental Health Criteria Document 134, IPCS. WHO, Geneva, 1-280.) identified renal dysfunction as the critical effect and a crude quantitative evaluation was presented. In the 1990's and 2000 several epidemiological studies have reported adverse health effects, sometimes at low environmental exposures to Cd, in population groups in Japan, China, Europe and USA (reviewed in other contributions to the present volume). The early identification of an important role of metallothionein in cadmium toxicology formed the basis for recent studies using biomarkers of susceptibility to development of Cd-related renal dysfunction such as gene expression of metallothionein in peripheral lymphocytes and autoantibodies against metallothionein in blood plasma. Findings in these studies indicate that very low exposure levels to cadmium may give rise to renal dysfunction among sensitive subgroups of human populations such as persons with diabetes.

Topics: Animals; Biomarkers; Cadmium; Dose-Response Relationship, Drug; Environmental Monitoring; Environmental Pollutants; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Kidney Diseases; Metallothionein; Osteomalacia; Protein Binding; Reproduction; Risk Assessment; Toxicology

Long term cadmium (Cd) exposure in occupational and general environments may give rise to kidney dysfunction. This effect is usually considered to be the critical effect, i. e. the effect that occurs at relatively low level of exposure. The present review focused on studies of the prevalence of cadmium-related kidney dysfunction among population groups residing in cadmium contaminated areas in China. Dose-response relationships were shown between UCd and the prevalence of increased levels of biomarkers in urine of renal tubular dysfunction such as urinary beta-2-microglobulin or N-acetyl-beta-d-glucosaminidase - NAG or urinary albumin, a biomarker of glomerular kidney dysfunction. Factors that influence these dose-response relationships include: 1) Metallothionein mRNA levels in peripheral blood lymphocytes, used as a biomarker of the ability of each person, to synthesize metallothionein (a protein known to provide intracellular protection against cadmium toxicity). 2) The occurrence of increased levels in blood plasma of autoantibodies against metallothionein. 3) Concomitant changes in glucose metabolism i e Type II diabetes. 4) Concomitant exposure to other nephrotoxic agents such as inorganic arsenic. Increased susceptibility in diabetics has been shown also in population groups in Europe. In persons with type II diabetes and increased levels of autoantibodies against metallothionein in blood plasma or in persons with concomitant exposure to environmental inorganic arsenic, indications of Cd-related kidney dysfunction was observed at UCd levels around 1 microg/g creatinine, levels found among "unexposed" population groups in many countries.

Topics: Arsenic; Cadmium; Environmental Exposure; Humans; Kidney Diseases; Metallothionein

Cadmium-induced nephrotoxicity develops at cadmium concentrations in the renal cortex of 10-300 micrograms/g wet weight. The actual concentration at which it develops depends on a number of factors, e.g., exposure route, chemical species of cadmium administered, rate of administration and simultaneous exposure to other metals. The role of these factors can be explained by a mechanism of cadmium nephrotoxicity in which both extracellular and intracellular metallothionein binding play an essential role. In reindeer used for human food, cadmium was shown to be bound to metallothionein-like proteins. If cadmium bound to such proteins enters the blood plasma via the gastrointestinal tract, this is of special toxicological significance. Metallothionein-bound cadmium in the plasma of experimental animals is efficiently transported to the kidney. Tubular dysfunction in the kidney following a normally tubulotoxic dose of cadmium bound to metallothionein was prevented by preinduction of metallothionein synthesis by small non-toxic doses of cadmium.

Topics: Animals; Cadmium; Cadmium Poisoning; Food Contamination; Kidney Diseases; Kidney Tubules; Metallothionein; Protein Binding; Reindeer; Tissue Distribution

Crucial points of in situ hybridization methods were pointed out for study on the kidney diseases at molecular level. As examples of in situ hybridization study on kidney, we introduced two cases: 1) expression of the hepatocyte growth factor gene during renal regeneration after unilateral nephrectomy, and 2) induction of the metallothionein gene expression by ischemic acute renal failure. We proposed an idea to establish a probe bank for the in situ hybridization study.

Topics: Acute Kidney Injury; Animals; Cloning, Molecular; DNA; Gene Expression; Hepatocyte Growth Factor; Humans; In Situ Hybridization; Kidney Diseases; Liver Regeneration; Metallothionein

Topics: Animals; Cadmium; Female; Fetus; Humans; Inactivation, Metabolic; Kidney; Kidney Diseases; Metallothionein; Placenta; Pregnancy

The requirement of zinc for humans was recognized in the early 1960s. The causes of zinc deficiency include malnutrition, alcoholism, malabsorption, extensive burns, chronic debilitating disorders, and chronic renal diseases; use of certain drugs such as penicillamine and, in some cases, diuretics; and genetic disorders such as acrodermatitis enteropathica and sickle cell disease. The requirement of zinc is increased in pregnancy and during growth. The clinical manifestations of severe zinc deficiency include bullous-pustular dermatitis, alopecia, diarrhea, emotional disorder, weight loss, intercurrent infections, and hypogonadism in males; zinc deficiency can be fatal if unrecognized and untreated. A moderate deficiency of zinc is characterized by growth retardation and delayed puberty in adolescents, hypogonadism in males, rough skin, poor appetite, mental lethargy, delayed wound healing, taste abnormalities, and abnormal dark adaptation. In mild cases of zinc deficiency in human subjects, we have observed oligospermia, slight weight loss, and hyperammonemia. Zinc is a growth factor. As a result of its deficiency, growth is affected adversely in many animal species and humans, probably because zinc is needed for protein and DNA synthesis and cell division. The effects of zinc and growth hormone on growth appear to be independent of each other in experimental animals. Whether zinc is required for the metabolism of somatomedin needs further investigation. Thyroid and adrenal functions do not appear to change as a result of zinc deficiency. Glucocorticoids may have an effect on zinc metabolism, although the clinical relevance of this effect is not known at present. In contrast, testicular function is affected adversely as a result of zinc deficiency in both humans and experimental animals. The effect appears to be a direct one since the hypothalamic-pituitary axis is intact, and may relate to the reduction in testicular size as a result of the need for zinc in cell division. In addition, zinc is required for the function of several testicular enzymes, although a specific role in steroidogenesis has not been identified. Zinc appears to have a role in the modulation of prolactin secretion, in the secretion and action of insulin, and in the production and biologic effects of thymic hormones. It is clear that the endocrine consequences of zinc deficiency are multiple, and that continued investigation should provide additional pathophysiologic and therapeutic i

Topics: Burns; Cell Membrane; Chronic Disease; Endocrine Glands; Enzymes; Female; Gastrointestinal Diseases; Genetic Diseases, Inborn; Growth; Humans; Immunity; Kidney Diseases; Metallothionein; Nucleic Acids; Pregnancy; Skin Diseases; Zinc

Cadmium has been shown to manifest its toxicity in human and animals by mainly accumulating in almost all of the organs and kidney is the main target organ where it is concentrated mainly in cortex. Environmental exposure of cadmium occurs via food, occupational industries, terrestrial and aquatic ecosystem. At molecular level, cadmium interferes with the utilization of essential metals e.g. Ca, Zn, Se, Cr and Fe and deficiencies of these essential metals including protein and vitamins, exaggerate cadmium toxicity, due to its increased absorption through the gut and greater retention in different organs as metallothionein (Cd-Mt). Cadmium transport, across the intestinal and renal brush border membrane vesicles, is carrier mediated and it competes with zinc and calcium. It has been postulated that cadmium shares the same transport system. Cadmium inhibits protein synthesis, carbohydrate metabolism and drug metabolizing enzymes in liver of animals. Chronic environmental exposure of cadmium produces hypertension in experimental animals. Functional changes accompanying cadmium nephropathy include low molecular weight proteinuria which is of tubular origin associated with excess excretion of proteins such as beta 2 microglobulin, metallothionein and high molecular weight proteinuria of glomerular origin (excretion of proteins such as albumin IgG, transferrin etc.). Recent data has shown that metallothionein is more nephrotoxic to animals. Cadmium is also toxic to central nervous system. It causes an alterations of cellular functions in lungs. Cadmium affects both humoral and cell mediated immune response in animals. Cadmium induces metallothionein in liver and kidney but under certain nutritional deficiencies like protein-calorie malnutrition and calcium deficiency, enhanced induction and greater accumulation of cadmium metallothionein has been observed.

Topics: Aging; Animals; Bone Diseases; Cadmium; Calcium; Central Nervous System Diseases; Chromium; Copper; Dietary Proteins; Drug Interactions; Environmental Exposure; Female; Half-Life; Humans; Hypertension; Immunity; Intestinal Absorption; Intestinal Diseases; Iron; Kidney Diseases; Liver; Lung; Male; Metallothionein; Ovary; Selenium; Sex Factors; Testis; Tissue Distribution; Vitamins; Zinc

Topics: Aging; Body Fluids; Cadmium; Cadmium Poisoning; Edetic Acid; Humans; Kidney Diseases; Kidney Glomerulus; Lead Poisoning; Mercury Poisoning; Metallothionein; Nephritis, Interstitial

Topics: Animals; Cadmium; Cadmium Poisoning; Environmental Exposure; Fishes; Food Analysis; Food Contamination; Fresh Water; Humans; Kidney Diseases; Metallothionein; Seawater

We investigated how zinc (Zn) supplementation affects metallothionein levels in the cortex and medulla of ischemic renal tissue of rats. We used adult male rats divided into four groups: group 1, untreated control; group 2, sham-operated; group 3, ischemia-reperfusion; group 4, ischemia-reperfusion + 5 g/kg Zn. Renal tissue was analyzed using immunostaining of rat metallothionein. Cells stained with metallothionein were counted and their percentage was calculated. We found that the Zn supplemented ischemia and reperfusion group exhibited a greater percentage of cells stained strongly for metallothionein in the renal cortex than all other groups. In the renal medulla, percentages of weak staining for metallothionein in the control and ischemia and reperfusion groups were greater than those in the sham and Zn-supplemented ischemia/reperfusion groups. Our findings indicate that the main effect of Zn in the renal tissue occurs in the cortex, while metallothionein synthesis in the renal medulla is unaffected.

Topics: Animals; Dietary Supplements; Ischemia; Kidney Diseases; Male; Metallothionein; Random Allocation; Rats; Rats, Wistar; Zinc Sulfate

Background The aim of this study was to investigate the effects of selenium, zinc, insulin, and metallothionein on oxidative damage and metallothionein (MT) gene expression levels in streptozotocin (STZ)-induced type 1 diabetic rats exposed to Cd. Methods Rats were categorized under eight groups (control, STZ, Cd, STZ + Cd, Group 5, Group 6, Group 7, and STZ + Cd + MT [n:8/group]) were used. After diabetes was induced by STZ (55 mg/kg, i.p.), Cd was administered (1 mg/kg CdCl, orally) for 4 weeks. In cadmium-treated groups selenium (Na2SeO3 1.5 mg/kg, i.p.), zinc (ZnSO4 10 mg/kg via oral gavage), insulin (insulin glargine, 2U/day, s.c.), and MT (1mg/kg, every other 10 days, s.c.) were administered. MT gene expression levels, MDA levels, GPx, SOD, and CAT activity levels were determined in liver and kidney tissues. Results MT gene expression and MDA levels increased (p < 0.05) while GPx and SOD activity levels decreased (p < 0.05) in STZ, Cd, and STZ + Cd groups. In Group 5, Group 6, Group 7, and Group 8 groups MT gene expression and MDA levels were decreased while GPx and SOD activity levels were increased (p < 0.05). CAT activity significantly increased (p < 0.05) in STZ + Cd group while there were no significance in other groups (p > 0.05). Compared to the control, Group 5, Group 6, Group 7, and Group 8 groups provided no difference for alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen and creatinine levels (p > 0.05). Conclusions Our results suggest that Se, insulin, Zn and MT may have protective effects against hepatotoxicity and nephrotoxicity caused by Cd exposure in diabetic rats by reducing oxidative stress and MT gene expression levels.

Topics: Animals; Cadmium; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Gene Expression Regulation; Insulin; Kidney Diseases; Liver Diseases; Male; Metallothionein; Oxidative Stress; Rats; Rats, Wistar; Selenium; Streptozocin; Zinc

To investigate heavy metal exposure in an industrial zone vs. a living quarter in Shanghai and explore the relationship between the heavy metal source and urine cadmium (Cd) and early kidney damage. Blood lead and urine Cd, manganese (Mn), mercury (Hg), arsenic (As) and EKD indexes were compared between residents in Exposure group (n = 168) and Control group (n = 168). It was found that PM

Topics: Acetylglucosaminidase; Adolescent; Adult; Albuminuria; Cadmium; China; Cystatin C; Environmental Exposure; Environmental Pollutants; Hepatitis A Virus Cellular Receptor 1; Housing; Humans; Industry; Kidney; Kidney Diseases; Metallothionein; Middle Aged; Retinol-Binding Proteins; Young Adult

The purpose of this research was to evaluate the protective effects of apocynin on renal ischemia/reperfusion (I/R) injury (RI/RI) in rats. Rats preconditioned with apocynin were subjected to renal I/R. Zinc levels in serum and renal tissues, blood urea nitrogen (BUN), and serum creatinine (Scr) were detected. We further measured the activity of superoxide dismutase (SOD); the content of malondialdehyde (MDA), IL-4, IL-6, IL-10, and TNF-α; and the expression of metallothionein (MT) in the renal tissues. Results indicated that the levels of MDA, IL-4, IL-6, IL-10, TNF-α, and MT in the kidney tissue and serum BUN and Scr levels in RI/RI group were significantly higher than those in sham-operated group, while the levels of serum Zn and kidney Zn and SOD were reduced in RI/RI group. Apocynin treatment further decreased the levels of MDA, IL-6, TNF-α, and serum BUN and Scr, whereas it significantly increased the levels of Zn, SOD, IL-4, IL-10, and MT in the kidney tissue and serum Zn. These findings suggest that apocynin might play a protective role against RI/RI in rats through regulating zinc level and MT expression involving in oxidative stress.

Topics: Acetophenones; Animals; Cytokines; Kidney; Kidney Diseases; Male; Metallothionein; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Superoxide Dismutase; Zinc

Cadmium (Cd)-intoxicated experimental animals exhibit impaired renal secretion of organic anions (OA) and cations (OC), indicating their transporters (Oats and Octs) in the proximal tubule (PT) basolateral membrane as possible targets of Cd. To correlate transport data from the literature with the expression of relevant transporters, we performed immunochemical and RT-PCR studies of renal Oats and Octs in the subchronic (treatment with CdCl2; 2 mg Cd/kg b.m./day, for 2 weeks) and acute (treatment with Cd-metallothionein (CdMT); 0.4 mg Cd/kg b.m., 6 or 12 h before killing) models of Cd nephrotoxicity. In the subchronic model, PT exhibited a minor loss of basolateral invaginations and overall unchanged expression of Na(+)/K(+)-ATPase and GAPDH proteins and mRNAs, while the expression of Oat and Oct proteins and their mRNAs was strongly downregulated. In the acute model, a time-related redistribution of basolateral transporters to the intracellular vesicular compartment was a major finding. However, 6 h following CdMT treatment, the total abundance of Oat and Oct proteins in the renal tissue remained unchanged, the expression of mRNAs decreased only for Oats, while a limited Oat1 and Na(+)/K(+)-ATPase immunoreactivity in the PT apical membrane indicated loss of cell polarity. As tested in rats treated with colchicine, the observed loss/redistribution of basolateral transporters in both models may be independent on microtubules. Therefore, the diminished renal secretion of OA and OC via PT in Cd nephrotoxicity may result from (a) limited loss of secretory surface (basolateral invaginations), (b) selective loss of Oats and Octs, and

Topics: Animals; Cadmium; Catecholamine Plasma Membrane Transport Proteins; Kidney; Kidney Diseases; Kidney Tubules, Proximal; Male; Metallothionein; Organic Anion Transport Protein 1; Organic Anion Transporters; Organic Cation Transport Proteins; Rats, Wistar; Sodium-Potassium-Exchanging ATPase; Toxicity Tests, Acute; Toxicity Tests, Subchronic

Carbon tetrachloride (CCl4) is commonly used as a chemical inducer of experimental liver injury. In addition, many studies showed that CCl4 can induce kidney damage. In the current study, we evaluated the protective effect of zinc (Zn) against CCl4-induced nephrotoxicity. We hypothesized that this protective effect would result from the ability of Zn to serve as an inducer of metallothionein (MT), a known endogenous scavenger of free radicals. We administered Zn (as ZnSO4) 50 mg/kg subcutaneously once daily for 3 successive days prior to a single intraperitoneal administration of CCl4 4 g/kg in male ddY mice. Our results showed that Zn pretreatment significantly decreased creatinine and blood urea nitrogen levels and reduced renal histopathological damage at 6 h post-CCl4 injection, observations consistent with enhanced antioxidative activity in the kidney. Moreover, kidney MT levels in the Zn+CCl4-treated group decreased by greater than 70% compared with levels in the Zn-alone group, implying that MT was consumed by CCl4-induced radicals. These findings suggest that prophylaxis with Zn protects mice from CCl4-induced acute nephrotoxicity, presumably by induction of MT, which in turn scavenges radicals induced by CCl4 exposure.

Topics: Animals; Blood Urea Nitrogen; Carbon Tetrachloride; Creatinine; Kidney; Kidney Diseases; Male; Malondialdehyde; Metallothionein; Mice; Zinc Sulfate

The purpose of this study was to investigate the underlying mechanism of metallothionein (MT) protection from depleted uranium (DU) using a proteomics approach to search for a DU toxicity-differential protein. MT-/- and MT+/+ mice were administrated with a single dose of DU (10 mg/kg, i.p.) or equal volume of saline. After 4 days, protein changes in kidney tissues were evaluated using a proteomics approach. A total of 13 differentially expressed proteins were identified using two-dimensional electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The validating results showed that the expression of aminoacylase-3 (ACY-3) and the mitochondrial ethylmalonic encephalopathy 1 (ETHE1) decreased significantly after DU exposure; in addition, the reduction in MT-/- mice was more significant than that in MT+/+ mice. The results also showed that exogenous ETHE1 or ACY-3 could increase the survival rate of human embryonic kidney 293 (HEK293) cells after DU exposure. A specific siRNA of ETHE1 significantly increased cell apoptosis rates after DU exposure, whereas exogenous ETHE1 significantly decreased cell apoptosis rates. In summary, ACY-3 and ETHE1 might involve in protection roles of MT. ETHE1 could be a new sensitive molecular target of DU-induced cell apoptosis.

Topics: Animals; Apoptosis; Gene Expression Regulation; HEK293 Cells; Humans; Kidney Diseases; Metallothionein; Mice; Mice, Knockout; Uranium

Depleted uranium (DU) has been widely used in both civilian and military activities, and the kidney is the main target organ of DU during acute high-dose exposures. In this study, the nephrotoxicity caused by DU in metallothionein-1/2-null mice (MT-/-) and corresponding wild-type (MT+/+) mice was investigated to determine any associations with MT. Each MT-/- or MT+/+ mouse was pretreated with a single dose of DU (10mg/kg, intraperitoneal injection) or an equivalent volume of saline. After 4days of DU administration, kidney changes were assessed. After DU exposure, serum creatinine and serum urea nitrogen in MT-/- mice significantly increased than in MT+/+ mice, with more severe kidney pathological damage. Moreover, catalase and superoxide dismutase (SOD) decreased, and generation of reactive oxygen species and malondialdehyde increased in MT-/- mice. The apoptosis rate in MT-/- mice significantly increased, with a significant increase in both Bax and caspase 3 and a decrease in Bcl-2. Furthermore, sodium-glucose cotransporter (SGLT) and sodium-phosphate cotransporter (NaPi-II) were significantly reduced after DU exposure, and the change of SGLT was more evident in MT-/- mice. Finally, exogenous MT was used to evaluate the correlation between kidney changes induced by DU and MT doses in MT-/- mice. The results showed that, the pathological damage and cell apoptosis decreased, and SOD and SGLT levels increased with increasing dose of MT. In conclusion, MT deficiency aggravated DU-induced nephrotoxicity, and the molecular mechanisms appeared to be related to the increased oxidative stress and apoptosis, and decreased SGLT expression.

Topics: Animals; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins; Biomarkers; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; Kidney; Kidney Diseases; Male; Metallothionein; Mice, Knockout; Oxidative Stress; Reactive Oxygen Species; Sodium-Glucose Transport Proteins; Time Factors; Uranyl Nitrate

The present study was conducted to elucidate the protective role of p-coumaric acid, a common dietary polyphenol against cadmium induced nephrotoxicity in rats. For the purpose of comparison, a standard reference drug silymarin (50 mg/kg b. wt) was used. In this experiment, the animals were divided into four groups, with each consisting of six animals. The animals in Group I animals received saline and served as a control group and those in Group II received cadmium chloride (3 mg/kg b. wt) subcutaneously once daily for 3 weeks, but Group III and IV animals received cadmium chloride followed by p-coumaric acid (100 mg/kg b. wt, oral) and silymarin (50 mg/kg b. wt, oral), respectively, daily for 3 weeks. At the end of the treatment, the animals were sacrificed, and the blood and kidney samples were collected. The results obtained in this study revealed the fact that the levels of lipid peroxidation, lysosomal enzymes, glycoprotein, cadmium and metallothionein were increased in the cadmium chloride alone treated rats and antioxidant status was found to be decreased, when compared to the control group. The levels of kidney functional markers (urea, uric acid and creatinine) were also found to be abnormal in serum and urine of cadmium chloride alone treated rats. On the other hand, the administration of p-coumaric acid along with cadmium chloride significantly protected the biochemical alterations as observed in the cadmium chloride alone treated rats as evidenced by histopathology. Thus, the oral administration of p-coumaric acid significantly protected the cadmium-induced nephrotoxicity in rats.

Topics: Acid Phosphatase; Animals; Antioxidants; Biomarkers; Cadmium; Cadmium Chloride; Coumaric Acids; Female; Glycoproteins; Kidney; Kidney Diseases; Lipid Peroxidation; Lysosomes; Male; Metallothionein; Oxidative Stress; Propionates; Rats; Rats, Wistar

Cadmium (Cd) is a toxic heavy metal and chronic exposure causes kidney injury. This study used DNA microarray analysis to examine gene expression in the kidney of mice chronically exposed to Cd. Female C57BL/6J mice were fed a 300 ppm Cd-containing diet or a control diet for 12 months. In comparison with control mice, the expression levels of 32 genes, including Hmox1 and Mt2, were elevated more than 2.0-fold, whereas 113 genes, including transport- and ubiquitination-related genes, were reduced less than 0.5-fold.

Topics: Animals; Cadmium Compounds; Female; Gene Expression; Gene Expression Profiling; Heme Oxygenase-1; Kidney; Kidney Diseases; Membrane Proteins; Metallothionein; Mice; Mice, Inbred C57BL; Oligonucleotide Array Sequence Analysis; Time Factors; Up-Regulation

Cisplatin (CDDP) is a potent anticancer agent, but severe renal toxicity can limit its use. We investigated the protective effect of cepharanthin (CE), a biscoclaurin alkaloid, on the renal toxicity of CDDP.. Mice were given CDDP along with CE. Effects of CE on CDDP toxicity were investigated by assaying markers of renal toxicity together with MT expression, and by histopathological examination of the kidney. MT-null mice were also examined.. CE induced expression of metallothionein (MT). Pre-administration of CE attenuated an increase in blood urea nitrogen (BUN) concentrations after the CDDP injection. A histochemical analysis demonstrated protection against CDDP-induced necrocytosis of kidney tissues by CE. The protective effect of CE did not occur in the MT-null mice.. Pretreatment with CE may reduce the renal toxicity of CDDP through expression of MT.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Benzylisoquinolines; Cell Line; Chlorocebus aethiops; Cisplatin; COS Cells; Kidney; Kidney Diseases; Male; Metallothionein; Mice; Mice, Inbred C57BL; RNA, Messenger; Up-Regulation

Cadmium (Cd) toxicity of the kidney varies between individuals despite similar exposure levels. In humans Cd is mainly bound to metallothioneins (MT), which scavenge its toxic effects. Here we analyzed whether polymorphisms in MT genes MT1A and MT2A influence Cd-related kidney damage.. In a cross-sectional study N=512 volunteers were selected from three areas in South-Eastern China, which to varying degree were Cd-polluted from a smelter (control area [median Cd in urine U-Cd=2.67 μg/L], moderately [U-Cd=4.23 μg/L] and highly [U-Cd=9.13 μg/L] polluted areas). U-Cd and blood Cd (B-Cd) concentrations were measured by graphite-furnace atomic absorption spectrometry. MT1A rs11076161 (G/A), MT2A rs10636 (G/C) and MT2A rs28366003 (A/G) were determined by Taqman assays; urinary N-Acetyl-beta-(D)-Glucosaminidase (UNAG) by spectrometry, and urinary β2-microglobulin (UB2M) by ELISA.. Higher B-Cd (natural log-transformed) with increasing number of MT1A rs11076161 A-alleles was found in the highly polluted group (p-value trend=0.033; all p-values adjusted for age, sex, and smoking). In a linear model a significant interaction between rs11076161 genotype and B-Cd was found for UNAG (p=0.001) and UB2M concentrations (p=0.001). Carriers of the rs11076161 AA genotype showed steeper slopes for the associations between Cd in blood and natural log-transformed UB2M (β=1.2, 95% CI 0.72-1.6) compared to GG carriers (β=0.30, 95% CI 0.15-0.45). Also for UNAG (natural log-transformed) carriers of the AA genotype had steeper slopes (β=0.55, 95% CI 0.27-0.84) compared to GG carriers (β=0.018, 95% CI -0.79-0.11).. MT1A rs11076161 was associated with B-Cd concentrations and Cd-induced kidney toxicity at high exposure levels.

Topics: Adult; Aged; Aged, 80 and over; beta 2-Microglobulin; Cadmium Poisoning; China; Cross-Sectional Studies; DNA; Environmental Pollutants; Female; Genotype; Humans; Kidney Diseases; Logistic Models; Male; Metallothionein; Middle Aged; Polymerase Chain Reaction; Polymorphism, Single Nucleotide

Adriamycin (ADR) is nephrotoxic. One component of ADR-induced nephropathy may be oxidative stress. This study used a recently developed line of transgenic mice (Nmt) on the FVB background strain, which over-express the antioxidant protein metallothionein (MT) in podocytes. Cultured podocytes from Nmt mice were resistant to H(2)O(2) injury, as judged by disruption of F-actin filaments. FVB control and transgenic mice received 11 mg/kg body weight ADR by tail vein injection and 24-h urine samples were then collected for albumin analysis. Also renal morphology was investigated by light and electron microscopy. Urine albumin analysis showed that ADR treatment significantly increased albuminuria in control mice, indicating that the FVB strain is sensitive to ADR nephropathy and Nmt mice were significantly protected from elevated albuminuria. Glomerular histopathology revealed that ADR reduced podocyte number and produced foot process effacement in FVB mice. The Nmt transgene protected podocyte numbers and podocyte foot processes from the effects of ADR. These results show that metallothionein can protect podocytes from ADR toxicity.

Topics: Animals; Doxorubicin; Gene Expression; Kidney Diseases; Metallothionein; Mice; Mice, Inbred Strains; Mice, Transgenic; Oxidative Stress; Podocytes; Reactive Oxygen Species

It is reported that metallothionein (MT) mRNA expression in human peripheral blood lymphocytes (HPBLs) could be used as exposure biomarkers in occupationally cadmium-exposed workers. Several MT isoforms have been identified in humans. The relationship between MT isoforms and cadmium toxicity has not been fully elucidated in occupational settings. In this study, the MT-IA, IE, IF, IX mRNA expressions in HPBLs were tested by RT-PCR technique, and the relationship between MT isoforms mRNA expression and cadmium-induced renal dysfunction was evaluated in cadmium-exposed workers. The MT-IE, IF, IX mRNA levels were found to increase with increasing blood cadmium (BCd) levels and MT-IA mRNA levels increased with increased urinary cadmium (UCd) levels. The MT-IE, IF, IX mRNA levels were significantly correlated with the BCd levels (P < 0.05), and MT-IA mRNA levels were significantly correlated with the UCd levels. This confirmed that MT-I isoforms mRNA expression in HPBLs is a biomarker of cadmium exposure and internal dose. The MT-IA mRNA levels were significantly correlated with renal dysfunction biomarkers, such as urinary beta2-microglobulin (Ubeta2-MG) (r = 0.294, P < 0.01) and urinary albumin (UALB) (r = 0.305, P < 0.01). The latter finding indicates that MT-IA mRNA expression in HPBLs may be used as a biomarker for renal dysfunction in occupational cadmium exposure.

Topics: Adult; beta 2-Microglobulin; Biomarkers; Cadmium; Humans; Kidney Diseases; Lymphocytes; Male; Metallothionein; Middle Aged; Occupational Exposure; Protein Isoforms; RNA, Messenger

5-Azactydine inhibits cell growth by direct cytotoxic action as well as by inhibition of DNA methyl transferase enzyme. Inhibitors of DNMT have been reported to potentiate the therapeutic activity of cisplatin in vitro. Dose dependent bone marrow toxicity, neurotoxicity and nephrotoxicity are the major side effects of cisplatin, limiting its use as an effective chemotherapeutic agent. The present study was aimed to reduce the nephrotoxic potential of cisplatin without compensating its potency. To best of our knowledge, this is the first report which shows that the combination of 5-azacytidine with cisplatin leads to remarkable reduction in nephrotoxicity, by involving inhibition of cisplatin induced metallothionein expression. 5-Azacytidine treatment with cisplatin leads to maximum reduction in tumor size in DMH induced colon cancer and tumor volume in DMBA induced breast cancer bearing SD rats. This combination regimen prevents phosphorylation and acetylation of histone H3 which may be involved in inhibition of aberrant gene expression in colon tumors. Further, 5-azacytidine potentiated cisplatin induced antitumor activity by involving decreased expression of pAKT, DNMT1 and an increased expression of p38 in colon tumors. Thus, combination of 5-azactydine with cisplatin attenuates the cisplatin induced nephrotoxicity and potentiates the anti-cancer activity which can have profound clinical implications.

Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Agents; Azacitidine; Blood Urea Nitrogen; Blotting, Western; Breast Neoplasms; Cell Nucleus; Cisplatin; Colonic Neoplasms; Creatinine; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; Drug Synergism; Drug Therapy, Combination; Female; Histones; Kidney Diseases; Male; Mammary Neoplasms, Experimental; Metallothionein; Neoplasms, Experimental; p38 Mitogen-Activated Protein Kinases; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley

To observe the relationship between urinary metallothionein excretion and osteal damage induced by cadmium in a general population.. The inhabitants living in both cadmium polluted and non-polluted areas were asked to participate in this study. Urinary cadmium (UCd) and blood cadmium (BCd) were measured by GF-AAS. Total cadmium(TCd)was evaluated with environmental cadmium exposure. URBP, UB2M, UALB and UMT were measured by ELISA method. UNAG, UNAGB were measured by fluorescence analysis method. Forearm bone mineral density in human were mensurated by SPA.. UMT can reflect the change of cadmium body burden. Renal dysfunction and osteoporosis would appear successively after high level of cadmium exposure. UMT had a complex relationship with bone mineral density which related to the amount of UMT excretion. The BMDLs of UCd were calculated using software of BMDS Versionl. 3.2 for these biomarkers. The values of BMDL of these biomarkers were arranged: UNAGB < UNAG < UB2M < UMT < URBP < Tscore < UALB.. Cadmium exposure could induce bone damage which occurred later than renal dysfunction related to cadmium exposure. UMT could be not only a specific and sensitive biological indicator of cadmium-induced renal dysfunction but also could reflect the damage on bone induced by cadmium.

Topics: Adult; Aged; Biomarkers; Bone Density; Bone Diseases; Cadmium; Environmental Exposure; Female; Humans; Kidney Diseases; Male; Metallothionein; Middle Aged

An herbal health care supplement, St John's Wort (SJW, Hypericum perforatum) has become widely used in the treatment of depression, and is known to interact with therapeutic drugs. Here we report a preventive effect of SJW on cisplatin nephrotoxicity in rats. Rats were given SJW (400 mg/kg/day, p.o.) for 10 consecutive days, and were injected with cisplatin (5 mg/kg, i.v.) on the day after the final SJW treatment. Cisplatin treatment increased the serum creatinine level, which is an index of nephrotoxicity, to 1.51+/-0.22 mg/dl (mean+/-SE) from 0.28+/-0.05 mg/dl (control) on day 5 after the cisplatin injection. This increase fell significantly to 0.86+/-0.13 mg/dl by pre-treatment with SJW. Cisplatin-induced histological abnormality of the kidney was blocked by pre-treatment with SJW. When SJW was administered for 10 days, the amounts of renal metallothionein (MT) and hepatic multidrug resistance protein 2 (Mrp2) were increased to 164.8+/-13.0% and 220.8+/-39.3% (mean+/-SE) of controls, respectively. GSH levels in the kidney and liver were not changed. Total and free cisplatin concentration in serum was not influenced by SJW treatment. In conclusion, the results suggest that pre-treatment with SJW may diminish cisplatin nephrotoxicity.

Topics: Animals; Antineoplastic Agents; ATP-Binding Cassette Transporters; Body Weight; Cell Membrane; Cisplatin; Creatinine; Drug Interactions; Glutathione; Hypericum; Kidney; Kidney Diseases; Male; Metallothionein; Rats; Rats, Wistar

Inflammation can play a key role in Cd-induced dysfunctions. Quercetin is a potent oxygen free radical scavenger and a metal chelator. Our aim was to study the effect of quercetin on Cd-induced kidney damage and metallothionein expression. The study was performed in Wistar rats that were administered during 9 weeks with either cadmium (1.2 mg Cd/kg/day, s.c.), quercetin (50 mg/kg/day, i.p.) or cadmium + quercetin. Renal toxicity was evaluated by measuring blood urea nitrogen concentration and urinary excretion of enzymes marker of tubular damage. Endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) renal expression were assessed by Western blot. Renal expression of metallothionein 1 and 2 (MT-1, MT-2) and eNOS mRNA was assessed by Northern blot. Our data demonstrated that Cd-induced renal toxicity was markedly reduced in rats that also received quercetin. MT-1 and MT-2 mRNA levels in kidney were substantially increased during treatment with Cd, being even higher when the animals received Cd and quercetin. Renal eNOS expression was significantly higher in rats receiving Cd and quercetin than in animals receiving Cd alone or in control rats. In the group that received Cd, COX-2 and iNOS expression was markedly higher than in control rats. In the group Cd+quercetin, no changes in COX-2 and iNOS expression were observed compared with the control group. Our results demonstrate that quercetin treatment prevents Cd-induced overexpression of iNOS and COX-2, and increases MT expression. These effects can explain the protection by quercetin of Cd-induced nephrotoxicity.

Topics: Animals; Cadmium Compounds; Chronic Disease; Cyclooxygenase 2; Disease Models, Animal; Enzyme Induction; Kidney Diseases; Male; Metallothionein; Nitric Oxide Synthase; Protective Agents; Quercetin; Rats; Rats, Wistar

Topics: Antigen-Antibody Complex; Autoantibodies; Cadmium; Humans; Kidney Diseases; Metallothionein

In order to study the validity of metallothionein (MT) gene expression in peripheral blood lymphocytes (PBLs) as a biomarker of cadmium exposure and susceptibility to renal dysfunction, MT mRNA levels were measured using reverse transcription polymerase chain reaction (RT-PCR) in PBLs from residents living in a cadmium-contaminated area. MT mRNA levels were found to increase with the increase of blood cadmium (BCd) and urinary cadmium (UCd) levels. Basal MT mRNA levels were significantly correlated with the logarithm of BCd levels and the logarithm of UCd levels confirming that MT expression in PBLs is a biomarker of cadmium exposure and internal dose. An inverse relationship was observed between in vitro induced MT-mRNA level in PBLs and urinary N-acetyl-beta-d-glucosaminidase (UNAG) suggesting that MT gene expression in PBLs may be used as a biomarker of susceptibility to renal toxicity of cadmium.

Topics: Adult; Aged; Biomarkers; Cadmium; Environmental Exposure; Female; Humans; Kidney Diseases; Lymphocytes; Male; Metallothionein; Middle Aged; RNA, Messenger

Attenuation of the renal toxicity of cis-diamminedichloroplatinum (CDDP) is important in the use of this effective but cytotoxic anticancer agent. We have previously shown that the renal toxicity of CDDP can be efficiently reduced by the induction of metallothionein (MT) by preadministration of bismuth compounds in mice. Bismuth subnitrate (BSN) is used as an antigastric ulcer agent and as an antidiarrheic agent, and is suitable for inducing MT in the kidney in cancer patients. However, due to the low absorption rate of Bi from the gastrointestinal tract, the efficacy of BSN in inducing renal MT is low. In the present study, we examined the effects of citrate as a vehicle for oral administration of BSN on the tissue distribution of Bi and induction of MT in the kidneys and tumors in mice inoculated with Meth-A fibrosarcoma. Renal levels of MT and Bi were markedly increased in the mice given BSN dissolved in citrate solution compared with those given BSN suspended in saline. On the other hand, the use of citrate increased Bi accumulation in the tumor only slightly and did not increase tumor MT levels. Administration of BSN with citrate efficiently depressed the renal toxicity of CDDP, but did not affect its antitumor activity. Since both BSN and citrate are used clinically as pharmaceuticals, the combination regimen of BSN and citrate may be readily applicable as a countermeasure against the adverse side effects of CDDP without affecting its antitumor activity.

Topics: Administration, Oral; Animals; Bismuth; Cisplatin; Citric Acid; Drug Synergism; Fibrosarcoma; Kidney; Kidney Diseases; Male; Metallothionein; Mice; Mice, Inbred Strains; Neoplasm Transplantation; Protective Agents; Tissue Distribution

Cadmium chloride (CdCl(2)) is a nephrotoxicant that causes damage to the proximal tubular epithelium. In vivo, it increases the permeability of epithelial surfaces, while in vitro, it acts on active trans-epithelial ion transport. The purpose of this study was to investigate CdCl(2) effects on a porcine renal proximal tubular epithelial cell line (LLC-PK1), and, in particular, to identify sensitive endpoints revealing damage both at the epithelial barrier level and at the molecular level. After exposure of the cells to CdCl(2), trans-epithelial resistance (TER) decreased while paracellular permeability (PCP) increased, indicating a structural alteration of the junctional complex. At the molecular level, we observed an increase in protective proteins, such as metallothioneins (MTs) and heat shock proteins (HSP70), starting from 25 microM CdCl(2), together with alterations in cytoskeleton organization. Production of reactive oxygen species (ROS) was also evident, indicating cellular oxidative stress. Our data indicate that CdCl(2) toxicity can be detected at the barrier level and at the molecular level at low concentrations, at which cytotoxicity assays are unable to show any damage. Therefore, these endpoints should prove very useful in studying heavy metal-induced acute toxicity. Exposure of the cells to higher concentrations of CdCl(2) (50 microM) revealed the initiation of apoptosis, mediated by caspase-3.

Topics: Acute Disease; Animals; Apoptosis; Biological Transport; Blotting, Western; Cadmium Chloride; Cadmium Poisoning; Cell Survival; Epithelial Cells; Flow Cytometry; HSP70 Heat-Shock Proteins; Immunohistochemistry; Kidney Diseases; Kidney Tubules, Proximal; L-Lactate Dehydrogenase; LLC-PK1 Cells; Metallothionein; Reactive Oxygen Species; Swine

Several studies have shown the role of thiol-rich proteins especially metallothionein (MT) in the therapeutic interventions against oxidative damage. Previously, we have provided strong evidence for the involvement of ROS in iron nitrilotriacetate (Fe-NTA)-induced renal toxicity, which may have relevance to its carcinogenicity. The purpose of this study was to evaluate the role of zinc metallothionein (Zn-MT) on the protection against Fe-NTA-induced renal oxidative damage. The results demonstrate that Zn-MT pretreatment provided protection against Fe-NTA-induced mortality in mice (40% protection). Similarly, Zn-MT pretreatment also provided protection against Fe-NTA-induced lipid peroxidation (26% inhibition, P < 0.001). It is proposed that Zn-MT protects kidney tissue against the noxious effect of Fe-NTA primarily by interference with lipid peroxides. It is concluded that Zn-MT may serve as an excellent physiological antioxidant against Fe-NTA-mediated renal oxidative damage.

Topics: Animals; Antioxidants; Ferric Compounds; Kidney; Kidney Diseases; Lipid Peroxidation; Lipid Peroxides; Male; Metallothionein; Mice; Nitrilotriacetic Acid; Oxidative Stress; Zinc

Cadmium is a potent hepatotoxicant for which neither effective preventive methods nor the mechanism of toxicity has been established. We investigated the preventive effect of dexamethasone against cadmium toxicity on cadmium-induced liver injury in rabbits. Pretreatment with dexamethasone at 1 mg/kg increased the rate of survival in rabbits administered 2.5 mg/kg iv cadmium. Cadmium induced acute severe liver injury characterized by hepatocellular necrosis, infiltration by inflammatory cells, and increases of plasma GOT, GPT, LDH, and LDH5. Dexamethasone mitigated the acute hepatotoxic effect of cadmium, but exacerbated cadmium-induced kidney dysfunction, with destruction of renal tubular cells and increases in excretion of protein, glucose, and amino acids into urine. The cadmium concentration in liver and kidney of rabbits administered cadmium was not changed by dexamethasone pretreatment. Although metallothionein mRNA expression induced by cadmium was not affected by dexamethasone in liver or kidney, cadmium-induced metallothionein protein production was augmented at the early phase in liver and decreased at the later phase in kidney. Neutrophilia observed after cadmium administration was enhanced initially by dexamethasone pretreatment. These results indicate that dexamethasone pretreatment potently prevented cadmium-induced liver injury, but exacerbated renal tubular dysfunction.

Topics: Amino Acids; Animals; Anti-Inflammatory Agents; Blood Urea Nitrogen; Cadmium; Chemical and Drug Induced Liver Injury; Creatinine; Dexamethasone; Disease Models, Animal; Drug Interactions; Female; Kidney; Kidney Diseases; Liver; Metallothionein; Proteinuria; Rabbits; Survival Rate; Time Factors

Metallothionein (MT) plays an important role in the detoxification of cadmium. To investigate the usefulness of MT gene expression in peripheral blood lymphocytes (PBLs) as a biomarker of cadmium exposure and susceptibility, reverse transcriptase-polymerase chain reaction was used to measure the MT gene expression in PBLs from cadmium-exposed workers. Both basal and induced MT expressions were found to increase with increased blood cadmium (BCd) and urinary cadmium (UCd) levels. Both basal and induced MT expression levels were significantly correlated with the logarithm of BCd and the logarithm of UCd levels. The dose-response relationship between internal dose of cadmium and MT expression suggested the validity of MT expression in PBLs as a biomarker of cadmium exposure. In vitro induced MT expression level in PBLs was found to be inversely related to the level of renal dysfunction indicator, urinary N-acetyl-beta-D-glucosaminidase (UNAG). The latter finding indicates that MT expression in PBLs may be a useful biomarker of susceptibility to renal toxicity of cadmium.

Topics: Acetylglucosaminidase; Adult; beta 2-Microglobulin; Biomarkers; Cadmium; Cells, Cultured; China; Dose-Response Relationship, Drug; Gene Expression; Humans; Kidney; Kidney Diseases; Leukocytes, Mononuclear; Male; Metallothionein; Occupational Diseases; Occupational Exposure; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spectrophotometry, Atomic

Metallothionein (MT) is a low-molecular-weight, sulfhydryl-rich, metal-binding protein that can protect against the toxicity of cadmium, mercury, and copper. However, the role of MT in arsenic (As)-induced toxicity is less certain. To better define the ability of MT to modify As toxicity, MT-I/II knockout (MT-null) mice and the corresponding wild-type mice (WT) were exposed to arsenite [As(III)] or arsenate [As(V)] either through the drinking water for 48 weeks, or through repeated sc injections (5 days/week) for 15 weeks. Chronic As exposure increased tissue MT concentrations (2-5-fold) in the WT but not in MT-null mice. Arsenic by both routes produced damage to the liver (fatty infiltration, inflammation, and focal necrosis) and kidney (tubular cell vacuolization, inflammatory cell infiltration, and interstitial fibrosis) in both MT-null and WT mice. However, in MT-null mice, the pathological lesions were more frequent and severe when compared to WT mice. This was confirmed biochemically, in that, at the higher oral doses of As, blood urea nitrogen (BUN) levels were increased more in MT-null mice (60%) than in WT mice (30%). Chronic As exposures produced 2-10 fold elevation of serum interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha levels, with greater increases seen by repeated injections than by oral exposure, and again, MT-null mice had higher serum cytokines than WT mice after As exposure. Repeated As injections also decreased hepatic glutathione (GSH) by 35%, but GSH-peroxidase and GSH-reductase were minimally affected. MT-null mice were more sensitive than WT mice to the effect of GSH depletion by As(V). Hepatic caspase-3 activity was increased (2-3-fold) in both WT and MT-null mice, indicative of apoptotic cell death. In summary, chronic inorganic As exposure produced injuries to multiple organs, and MT-null mice are generally more susceptible than WT mice to As-induced toxicity regardless of route of exposure, suggesting that MT could be a cellular factor in protecting against chronic As toxicity.

Topics: Administration, Oral; Animals; Arsenic; Blood Urea Nitrogen; Caspase 3; Caspases; Chemical and Drug Induced Liver Injury; Female; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Injections, Subcutaneous; Interleukin-1; Interleukin-6; Kidney; Kidney Diseases; Liver; Male; Metallothionein; Mice; Mice, Knockout; Organ Size; Tumor Necrosis Factor-alpha

Cadmium (Cd) and arsenic (As) are important inorganic toxicants in the environment. Humans certainly have the potential to be exposed to the mixtures of Cd and As, but the toxicological interactions of these inorganic mixtures are poorly defined. Metallothionein (MT) is a cysteine-rich, metal-binding protein that plays an important role in Cd detoxication, but its role in As toxicity is less certain. To examine the role of MT in Cd- and/or As-induced nephrotoxicity, MT-I/II-knockout (MT-null) mice and background-matched wild-type (WT) mice were fed CdCl(2) (100 ppm Cd) in the diet, NaAsO(2) (22.5 ppm As) in the drinking water, or Cd plus As for 4 months. Subsequently, nephrotoxicity was examined by morphological and biochemical techniques. Chronic exposure to Cd produced more renal toxicity than As, and the combination of Cd and As produced even more renal injury than caused by either of the chemicals given alone. In mice receiving Cd plus As, proximal tubule degeneration and atrophy, glomerular swelling and interstitial fibrosis were more severe than those produced by either inorganic. Furthermore, lack of MT rendered MT-null mice more sensitive than WT mice to the nephrotoxicity produced by chronic Cd- and/or As-exposure. MT-null mice were especially susceptible to the toxicity produced by the combination of Cd and As, as evidenced by decreased body weight, enzymuria, glucosuria, proteinuria and nephropathy. In conclusion, this study indicates that As may potentiate Cd nephrotoxicity during the long-term, combined exposure, and that intracellular MT plays a role in decreasing the nephropathy of combined exposure to Cd and As.

Topics: Acetylglucosaminidase; Administration, Oral; Animals; Arsenic; Body Weight; Cadmium; Drug Administration Schedule; Drug Synergism; Glycosuria; Kidney; Kidney Diseases; Liver; Male; Metallothionein; Mice; Mice, Knockout; Organ Size; Proteinuria

Chronic exposure to cadmium (Cd) via food and drinking water is a major human health concern. We have previously shown that metallothionein (MT), a metal-binding protein, plays an important role in protecting against Cd toxicity produced by repeated sc injections. However, it is unclear whether MT protects against Cd-induced nephrotoxicity following chronic oral exposure, a route with obvious human relevance. To clarify this issue, MT-I/II knockout (MT-null) and background-matched wild-type (WT) mice were allowed free access to drinking water containing CdCl(2) (30, 100, and 300 ppm Cd), or feed containing CdCl(2) (100 ppm Cd) for 6 months, and the resultant nephrotoxicity was examined. Chronic oral Cd exposure produced a dose-dependent accumulation of Cd in liver and kidney of WT mice, reaching levels up to 50 microg Cd/g tissue. Immunohistological localization of renal MT indicated that chronic oral Cd exposure in WT mice greatly increased MT in the proximal tubules and the medulla, with cellular localization in both the cytoplasm and nuclei. As expected, no MT was detected in kidneys of MT-null mice. After 6 months of Cd exposure, tissue Cd concentrations in MT-null mice were only about one-fifth of that in WT mice. Even though the renal Cd concentrations were much lower in the MT-null mice, they were more sensitive than WT mice to Cd-induced renal injury, as evidenced by more severe nephropathic lesions, increased urinary excretion of gamma-glutamyl-transferase and glucose, and elevated blood urea nitrogen. Six months of Cd exposure to MT-null animals resulted in greater increases in renal caspase-3 activity, an indicator of apoptosis, than to WT mice. In conclusion, this study demonstrates that lack of MT renders MT-null mice vulnerable to Cd-induced nephrotoxicity after chronic oral exposure, the primary route of human Cd exposure.

Topics: Animals; Blood Urea Nitrogen; Cadmium; Chronic Disease; Female; Immunohistochemistry; Kidney; Kidney Diseases; Kidney Function Tests; Male; Metallothionein; Mice; Mice, Knockout; Organ Size

The objective of this study was to correlate hepatic and renal cadmium (Cd) accumulation, Cd-binding capacity of metallothionein (MT) and lipid peroxidation with the tissue injury in the male bank voles raised under short (8 h light/16 h dark) and long (16 h light/8 h dark) photoperiods that affect differently Cd accumulation and MT induction in these rodents. The animals were exposed to dietary Cd (0, 40 and 80 microg/g) for 6 weeks. The accumulation of Cd in the liver and kidneys appeared to be dose-dependent in bank voles from the two photoperiod groups; however, the short-photoperiod animals exhibited significantly higher concentrations of Cd in both organs than the long-photoperiod bank voles. Cd-Binding capacity of MT in the liver and kidneys of bank voles from the long photoperiod was sufficiently high to bind and detoxify all Cd ions, while in the animals fed 80 microg Cd/g under the short photoperiod, the concentrations of Cd in both organs exceeded (by about 10 microg/g) the MT capacity. However, similar histopathological changes in the liver (a focal hepatocyte swelling and granuloma) and kidneys (a focal degeneration of proximal tubules) occurred in Cd-80 bank voles from the two photoperiods. Likewise, in either photoperiod group, dietary Cd brought about a similar, dose-dependent decrease in the hepatic and renal lipid peroxidation, which paralleled closely that of the iron (Fe) concentrations. These data indicate that: (1) MT does not protect the liver and kidneys against Cd-induced injury in the bank vole exposed to the higher level of dietary Cd; and (2) lipid peroxidation cannot be responsible for the tissue damage. It is hypothesized that dietary Cd produces histopathological changes indirectly, through depressing the tissue Fe and Fe-dependent oxidative processes.

Topics: Animals; Arvicolinae; Body Weight; Cadmium; Chemical and Drug Induced Liver Injury; Copper; Diet; Iron; Kidney; Kidney Diseases; Light; Lipid Peroxidation; Liver; Liver Diseases; Male; Metallothionein; Organ Size; Photoperiod; Zinc

Exposure to cadmium (Cd) can result in nephrotoxicity and osteotoxicity. Because Cd-induced nephrotoxicity involves oxidative stress and caloric restriction decreases oxidative stress, we examined whether reduced caloric intake will protect against Cd-induced nephrotoxicity. In addition, the protection against the osteotoxicity was also examined. Male and female Sprague-Dawley rats were provided drinking water containing 100 mg Cd/l. Since fluid intake relative to the body weight was higher in females as compared to the males, the Cd concentration in their water was reduced to 80 mg/l after 3 months and 65 mg/l after 6.5 months. During the 27 month exposure period the males and females consumed a total of about 5 g Cd/kg body weight. Food was restricted to 20 g/day after the first 3 months. During the unrestricted food intake period Cd exposure reduced the bone density in females by 23%, with a partial recovery and stabilization during the caloric restriction phase. Hepatic and renal Cd accumulation and corresponding metallothionein (MT) levels were very similar in both sexes. The reported critical Cd concentration for nephrotoxicity was reached by 9 months. Renal MT levels were maximum at this time. Despite a 1.5-fold increase in renal Cd concentration over the next 18 months, there was no significant increase in renal MT levels. In spite of high renal Cd levels and lack of availability of sufficient MT, there was no sign of nephrotoxicity, as measured by urinary protein and glucose excretion. It is concluded that caloric restriction prevents Cd-induced nephrotoxicity and also appears to control the osteotoxicity of Cd.

Topics: Animals; Body Weight; Bone Density; Bone Diseases; Cadmium; Drinking; Energy Intake; Female; Kidney; Kidney Diseases; Liver; Male; Metallothionein; Rats; Rats, Sprague-Dawley; Sex Factors

Metallothionein (MT) is a low-molecular-weight, cysteine-rich, metal-binding protein. Induction of MT has been proposed to be an important adaptive mechanism in decreasing Cd toxicity. MT has been shown to protect against CdCl2-induced lethality and hepatotoxicity; however, MT does not protect against acute CdMT-induced nephrotoxicity. This study was aimed at clarifying the role of metallothionein in chronic CdMT-induced renal injury. Wild type and MT-I/II knockout (MT-null) mice were therefore given sc injections of CdMT (25 and 100 microg Cd/kg) or saline daily, 6 times/week for 6 weeks, and renal injury was evaluated. Multiple injections of CdMT to wild-type mice resulted in renal Cd concentrations up to 120 microg/g kidney, along with a 100-fold increase in renal MT (450 microg/g kidney). In contrast, renal Cd concentration in MT-null mice administered multiple injections of CdMT reached a much lower level than in wild-type mice (<10 microg/g kidney). Although less Cd accumulated in their kidneys, MT-null mice were more susceptible than wild-type mice to CdMT-induced nephrotoxicity, as indicated by increased urinary excretion of protein and N-acetyl-beta-D-glucosaminidase, as well as by elevated blood urea nitrogen levels. At the higher daily dose of CdMT (100 microg Cd/kg), kidneys of MT-null mice were enlarged. Chronic CdMT administration eventually damaged the entire kidney, which included glomerular swelling, interstitial inflammation, edema, tubular cell degeneration, and atrophy. In contrast to a single injection of CdMT that produces proximal tubular necrosis, chronic injection of CdMT results in tubular cell apoptosis in both wild-type and MT-null mice. These data indicate that chronic CdMT administration produces similar renal injury to that observed after chronic CdCl2 administration, and that intracellular MT protects against nephrotoxicity produced by chronic CdMT administration.

Topics: Acetylglucosaminidase; Animals; Blood Urea Nitrogen; Cadmium; Dose-Response Relationship, Drug; Drug Interactions; Homozygote; Kidney Diseases; Metallothionein; Mice; Mice, Knockout; Proteinuria; Rats; Time Factors

Streptozotocin-induced diabetic rats and normal non-diabetic (ND) rats were exposed to cadmium chloride in drinking water in doses of 0, 50 and 100 ppm for 90 days. There was a dose-related increase in urinary protein and enzymes in the diabetic group, but an increase in proteinuria only in the high exposure subgroup of the ND group. It is suggested that diabetic rats induced by streptozotocin are more susceptible to cadmium nephrotoxicity than normal (ND) rats. Metallothionein synthesis in liver was estimated to be similar in both the diabetic and non-diabetic groups after exposure to cadmium. Less excretion of cadmium in urine and greater accumulation of cadmium in kidney were observed in the diabetic group, and this may be one of the mechanisms underlying the susceptibility of diabetic animals to the effects of cadmium. Further biochemical and histological studies are required in order to explain the detailed events involved in inducing such changes in the toxicokinetics of cadmium.

Topics: Acetylglucosaminidase; Administration, Oral; Animals; Cadmium; Cadmium Chloride; Chromatography; Diabetes Mellitus, Experimental; Disease Susceptibility; Drinking; Female; gamma-Glutamyltransferase; Kidney; Kidney Diseases; Liver; Metallothionein; Proteinuria; Rats; Rats, Wistar; Zinc

Kidney is the main target organ of Cd toxicity in humans. Cd-induced nephrotoxicity is thought to be caused by the Cd-metallothionein complex (CdMT) that "leaks" out of the liver and is taken up by the kidney. A single injection of CdMT has therefore been used as a model to study Cd nephropathy for the last 20 years. However, our recent studies reveal discrepancies between renal Cd concentration and nephrotoxic potencies of CdCl2 and CdMT. This study was further designed to critically evaluate whether a single injection of CdMT is an appropriate model to study the mechanism of chronic CdCl2 nephropathy. Age-matched rats were given multiple sc injections of either CdCl2 (0.8 and 1.2 mg Cd/kg) or CdMT (0.05 mg Cd/kg) daily, 6 days/week for 6 weeks, or a single injection of CdMT (0.2-0.6 mg Cd/kg i.p. for 24 h), and the nephrotoxicity was compared. Histologically, chronic CdCl2 or CdMT administration produced damage to the whole kidney, including tubular cell degeneration, apoptosis, and atrophy; interstitial inflammation; glomerular swelling; and sclerosis. In contrast, acute CdMT injection produced severe proximal tubule necrosis as the major feature of its toxicity. Biochemically, chronic exposure to Cd produced polyuria and calciuria, while proteinuria, glucosuria, and enzymuria were mild (2-5x). In contrast, acute CdMT nephrotoxicity was characterized by marked increases in urinary protein (13x), glucose (25x), N-acetyl-beta-d-glucosaminidase (28x), lactate dehydrogenase (100x), and gamma-glutamyltranspeptidase (160x). Serum levels of creatinine and blood urea nitrogen were unchanged following chronic Cd exposure but were markedly elevated (5x) after acute injection of CdMT. Chronic exposure to either CdCl2 or CdMT produced nephrotoxicity at renal Cd concentration of 85 to 110 micrograms/g kidney, while acute CdMT injection produced nephrotoxicity at only 5 to 7 micrograms/g kidney. In conclusion, the present study indicates that the features and mechanisms of renal injury from chronic Cd exposure are quite different from those produced by a single injection of CdMT. Therefore, it is proposed that acute CdMT injection is not an appropriate model for the study of chronic Cd-induced nephrotoxicity.

Topics: Animals; Body Weight; Cadmium Chloride; Female; Glycosuria; Kidney; Kidney Diseases; Metallothionein; Proteinuria; Rats; Rats, Sprague-Dawley

Chronic human exposure to Cd results in kidney injury. It has been proposed that nephrotoxicity produced by chronic Cd exposure is via the Cd-metallothionein complex (CdMT) and not by inorganic forms of Cd. If this hypothesis is correct, then MT-null mice, which cannot form CdMT, should not develop nephrotoxicity. Control and MT-null mice were injected s.c. with a wide range of CdCl2 doses, six times/week for up to 10 weeks, and their renal Cd burden, renal MT concentration, and nephrotoxicity were quantified. In control mice, renal Cd burden increased in a dose- and time-dependent manner, reaching as high as 140 microg Cd/g kidney, along with 150-fold increases in renal MT concentrations, reaching 800 microg MT/g kidney. In MT-null mice, renal Cd concentration (10 microg/g) was much lower, and renal MT was nonexistent. The maximum tolerated dose of Cd in MT-null mice was approximately one-eighth that of controls. MT-null mice were more susceptible than controls to Cd-induced renal injury, as evidenced by increased urinary excretion of protein, glucose, gamma-glutamyltransferase, and N-acetyl-beta-D-glucosaminidase, as well as by increased blood urea nitrogen levels. Kidneys of Cd-treated mice were enlarged and histopathology showed various types of lesions, including proximal tubular degeneration, apoptosis, atrophy, interstitial inflammation, and glomerular swelling. These lesions were more severe in MT-null than in control mice, mirroring the biochemical analyses. These data indicate that Cd-induced renal injury is not necessarily mediated through the CdMT complex and that MT is an important intracellular protein in protecting against chronic Cd nephrotoxicity.

Topics: Acetylglucosaminidase; Animals; Body Weight; Cadmium Chloride; Cadmium Radioisotopes; Female; gamma-Glutamyltransferase; Glycosuria; Kidney; Kidney Diseases; Male; Metallothionein; Mice; Mice, Knockout; Proteinuria

Arsenic and cadmium are both priority hazardous substances and human carcinogens. Although there is the potential for simultaneous exposure to both metals, the interactions of cadmium and arsenic are not well defined. We examined the toxicity of these metals when given alone or in alternating sequence to adult male Fischer rats. In the first study, a non-toxic dose of arsenic (22.5 micromol NaAsO2/kg, s.c.) was given 24 h before cadmium (10, 20, or 30 micromol CdCl2/kg, s.c.) and toxicity was assessed 24 h later. Arsenic pretreatment markedly reduced mortality in rats given the high dose of cadmium (9 survivors/10 treated) compared to rats given cadmium alone (2/10). Arsenic pretreatment also reduced cadmium-induced hepatotoxicity, as indicated by serum glutamic oxalacetic transaminase (SGOT) activity, and markedly reduced cadmium-induced testicular hemorrhagic necrosis. Arsenic pretreatment produced an 8-fold increase in hepatic levels of metallothionein (MT), a metal-binding protein often associated with cadmium tolerance. In the second study, a non-toxic dose of cadmium (3 micromol CdCl2/kg, s.c.) was given 24 h before arsenic (68, 79, 84, or 90 micro/mol NaAsO2/kg. s.c.) and toxicity was assessed 24 h later. Cadmium pretreatment did not alter the lethality of the high dose of arsenic and had no effect on arsenic-induced hepatotoxicity. Although cadmium pretreatment had no effect on arsenic toxicity, it produced large increases in hepatic MT (26-fold) before the arsenic challenge and greatly enhanced MT induction after the challenge. Thus, even though both arsenic and cadmium induce MT synthesis, only arsenic pretreatment protects against cadmium intoxication, and cadmium pretreatment does not effect arsenic toxicity. Thus, toxic interactions of arsenic and cadmium appear to depend on the sequence of exposure.

Topics: Animals; Arsenic; Cadmium; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Drug Interactions; Kidney Diseases; Male; Metallothionein; Necrosis; Rats; Rats, Inbred F344; Testis

To elucidate the protective role of metallothionein (MT) in the prevention of cisplatinum (cis-DDP) toxicity, we investigated the lethal and renal toxicities caused by cis-DDP in MT-null transgenic mice in comparison with wild-type control mice, and examined the effect of pretreatment with bismuth nitrate or zinc sulfate on the cis-DDP nephrotoxicity. The MT-null mice were of mixed 129 Ola and C57BL/6 genetic background. Since no differences in cis-DDP nephrotoxicity were observed between these strains, C57BL/6J mice were used as the wild-type control. The basal MT levels in the kidneys were negligible in the MT-null mice and 2.93 +/- 0.77 micrograms/g tissue in the C57BL/6J mice. In terms of both the lethal and renal toxicities of cis-DDP, MT-null mice were far more sensitive than C57BL/6J mice. Preinduction of renal MT synthesis by administration of bismuth nitrate or zinc sulfate protected C57BL/6J mice from cis-DDP nephrotoxicity. In the case of MT-null mice, however, renal MT could not be induced by pretreatment with these metal compounds, and renal toxicity of cis-DDP was not prevented by this pretreatment. These results suggest that MT is an important factor with the potential to suppress the development of cis-DDP toxicity.

Topics: Animals; Antineoplastic Agents; Bismuth; Blood Urea Nitrogen; Cisplatin; Creatinine; Female; Injections, Intraperitoneal; Kidney; Kidney Diseases; Metallothionein; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Nitrates; Sulfhydryl Compounds; Zinc Sulfate

Biomarkers for pathophysiological responses to heavy metals are described with special reference to immunotoxic responses to them. Autoantibody induction in animals by exposure to cadmium is exemplified and discussed on its relevance to pathogenesis of cadmium-induced renal disease. The availability of autoantibodies as a mechanism-oriented biomarker is discussed further in association with cases of autoantibody induction in heavy metal workers.

Topics: Animals; Autoantibodies; Autoimmune Diseases; Biomarkers; Cadmium; Humans; Immunotoxins; Kidney Diseases; Metallothionein; Metals, Heavy; Occupational Diseases

Protection against the development of nephrotoxicity following the administration of cadmium-metallothionein (CdMT) at a dose of 0.4 mg Cd per kg body weights was studied in streptozotocin (STZ)-induced diabetic rats. Six groups of Wistar male rats were used (Groups A and B, Groups A1 and C, and Groups A2 and D were injected intraperitoneally with STZ at doses of 0, 50 and 100 mg/kg, respectively, and then 6 days later, Groups B, C and D were injected subcutaneously with CdMT). Proteinuria, albuminuria and transferrinuria were observed after the administration of CdMT, and a dose-related decrease following the increased STZ dose was seen in Groups B, C and D. The concentrations of metallothionein (MT) and zinc (Zn) in liver and kidney were dose-dependently increased in Groups B, C and D. Induction of increased MT synthesis in liver and kidney as the result of the STZ treatment was observed in this study. In particular, a remarkable increase in liver MT concentration was induced by STZ, and transport to the kidney of MT synthesized in liver may perhaps explain the protection against cadmium nephrotoxicity in STZ-induced diabetic rats.

Topics: Animals; Cadmium; Chromatography, Gel; Cytosol; Diabetes Mellitus, Experimental; Kidney; Kidney Diseases; Liver; Male; Metallothionein; Metals; Proteinuria; Rats; Rats, Wistar; Streptozocin; Transferrin; Urination

Cadmium (Cd) chloride was intravenously injected at doses of 0.05 and 0.5 mg/kg/day in ovariectomized rats for 50 weeks, and the chronic Cd exposure-induced nephrotoxicity and anemia were investigated. The rats treated with 0.05 mg/kg Cd showed no apparent hematological, urinary, and histopathological abnormalities. In the 0.5-mg/kg group, renal tubular disorders became marked at 16 weeks, and cortical fibrosis with glomerular dysfunction appeared at 50 weeks. Anemia occurred at 12 weeks in the 0.5-mg/kg group and became increasingly marked with time. The mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were decreased at 12 and 25 weeks; however, the decreases of MCV and MCH disappeared at 50 weeks. A slight decrease in mean corpuscular hemoglobin concentration was noted at 50 weeks. The blood chemistry from the same group revealed a decrease in plasma iron levels and an increase in total iron binding capacity throughout the administration period. The erythropoietin (EPO) level was increased as the hemoglobin level decreased at 12 weeks, whereas the EPO level was not elevated even when the hemoglobin level was decreased at 50 weeks. These findings showed that renal anemia also occurred in addition to the iron deficiency anemia at 50 weeks.

Topics: Anemia; Animals; Body Weight; Cadmium; Cadmium Poisoning; Drinking; Erythropoietin; Female; Ferritins; Hemoglobins; Injections, Intravenous; Kidney; Kidney Diseases; Liver; Metallothionein; Ovariectomy; Rats; Rats, Sprague-Dawley; Urine

Mice pretreated with Zn have increased renal metallothionein (MT) levels and are protected from CdMT nephrotoxicity. To determine whether MT is important in this Zn-induced protection against CdMT-induced nephrotoxicity, MT-transgenic mice that have high levels of MT in their kidneys (10-fold over control mice) have been studied to determine whether they are resistant to CdMT-induced nephrotoxicity. Mice were injected with CdMT (0.1-0.6 mg Cd/kg, iv) and kidney injury was evaluated 24 hr later. CdMT produced renal toxicity in a dose-dependent manner. At a nephrotoxic dose of CdMT (0.4 mg Cd/kg), urinary protein and glucose excretion were increased 30- and 60-fold, respectively, in control mice. However, similar increases in protein and glucose excretion were also observed in MT-transgenic mice. CdMT also induced a similar dose-dependent proximal tubular cell necrosis in both control and MT-transgenic mice in a dose-dependent manner. Treatment of control mice with Zn (100 micromol/kg, sc x 2 days) increased renal MT to levels similar to those of untreated MT-transgenic mice and protected against CdMT-induced renal injury. Furthermore, when Zn (25-100 micromol/kg, sc) was given immediately before CdMT injection (i.e., without preinduction of MT), it was still effective in preventing CdMT nephrotoxicity. We conclude that Zn-induced protection against CdMT nephrotoxicity does not appear to be due to induction of renal MT.

Topics: Animals; Dose-Response Relationship, Drug; Glycosuria; Kidney; Kidney Diseases; Male; Metallothionein; Mice; Mice, Inbred C57BL; Mice, Transgenic; Proteinuria

The cadmium-metallothionein (CdMT) injection model was used to examine whether multiple short-interval injections of CdMT, instead of a single dose, could better reproduce the features of chronic exposure to inorganic cadmium. Male Wistar rats were given an initial CdMT dose and four subsequent doses subcutaneously at 2-h intervals. A control group, given saline, was compared with a low dose group (0.2 + 4 x 0.1 mg Cd/kg b.w.) and high dose group (0.4 + 4 x 0.1 mg Cd/kg b.w.). Nephrotoxic effects were seen at the high dose. A marked proteinuria began 6-12 h after the first injection and extended to day 9. A progressive, unreversed calciuria appeared at 6 h and reached its maximum at day 13. This was a marked increase in duration compared with the transient peaks of proteinuria and calciuria observed in previous single dose studies. The unreversed calciuria and the marked proteinuria are suggestive of residual tubular damage, which may be irreversible. In conclusion, the model with multiple short-interval CdMT injections more closely reproduces the situation in long-term exposure to inorganic cadmium, compared to the single dose models previously employed.

Topics: Animals; Dose-Response Relationship, Drug; Drug Administration Schedule; Injections, Subcutaneous; Kidney Diseases; Kidney Tubules; Male; Metallothionein; Proteinuria; Rats; Rats, Wistar

Cadmium-metallothionein (Cd-MT) is selectively distributed to the kidney, producing nephropathy similar to that seen following chronic exposure to Cd. The critical concentration of Cd after an injection of Cd-MT (about 10 micrograms/g) is much lower than that following chronic Cd exposure (130-200 micrograms/g). To investigate whether administration of Cd-MT at nonacute toxic dosages can induce chronic nephrotoxicity similar to inorganic Cd, i.e., renal accumulation of Cd and nephropathy, repeated injections of 109Cd-MT at two doses, 25 or 80 micrograms/kg/day, were given to rats. The concentration of 109Cd in kidney was 7-10 times higher than that in liver at each treatment level. Concentrations of 109Cd were highest in the kidney and reached a plateau following repeated injections of 109Cd-MT at both doses. The renal 109Cd levels found here (200 and 140 micrograms/g) were in the same range as the concentrations found at a plateau following repeated CdCl2 injection. Indications of nephrotoxicity following repeated injections of 109Cd-MT did not occur until renal Cd leveled off. The majority of intracellular Cd is sequestered by endogenous MT in the kidney. After renal Cd leveled off, the hepatic concentration of 109Cd did not markedly increase, but urinary excretion of 109Cd increased significantly. In addition both urinary protein and glucose also increased significantly, indicating that the appearance of nephrotoxicity is dependent on renal Cd saturation following long-term administration of Cd-MT. This is similar to what is seen following chronic inorganic cadmium exposure. These results support the suggestion that Cd-MT plays a major role in the initiation and development of Cd-induced renal damage.

Topics: Animals; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Injections, Intravenous; Injections, Subcutaneous; Kidney; Kidney Diseases; Liver; Male; Metallothionein; Rats; Rats, Wistar; Tissue Distribution

We studied nephrotoxicity following a single injection of cisplatin (CDDP) at low dose (1 mg/kg) in two groups of rats aged 52 weeks (adult, A group) and 9 weeks (young, Y group). Renal platinum (Pt) was detectable in both groups 3 h after the CDDP injection, and, from 6 h to 3 d after injection, its level in the A group was higher than that in the Y group. Compared with the levels in age-matched normal rats (non-treated rats examined at time zero), the plasma urea nitrogen and creatinine levels in the A group were significantly increased, beginning 3 d after CDDP injection, while those in the Y group showed little change for 10 d after injection. Beginning 3 d after CDDP injection, the level of renal metallothionein in the Y group increased, while that in the A group decreased remarkably. The renal tissue levels of the heavy metals Zn, Cu, Mn showed similar patterns. There were no significant changes in the renal lipid peroxide (LPO) level in either the A and Y group at any time measured after CDDP injection compared with the value in the respective age-matched untreated group. Morphological evaluation demonstrated degeneration of the proximal tubules in the A group 3 d after CDDP injection. These results suggested that the renal disorders observed following CDDP injection in the A group were caused by mechanisms other than LPO such as decreased tissue metabolic function associated with aging.

Topics: Aging; Animals; Antineoplastic Agents; Blood Urea Nitrogen; Cisplatin; Creatinine; Kidney; Kidney Diseases; Lipid Peroxides; Male; Metallothionein; Metals; Rats; Rats, Sprague-Dawley

In contrast to inorganic Cd, acute iv administration of Cd bound to metallothionein (CdMT) concentrates in renal tissue. This uptake of CdMT produces functional and morphological changes in kidneys, similar to those observed after chronic exposure to inorganic Cd. In order to examine the importance of the metal component of MT in the renal uptake of MT, the renal concentration of 35S after administration of [35S]ZnMT and [35S]CdMT was compared. Renal uptake of 35S from both CdMT and ZnMT was very rapid, with peak concentrations observed 15-30 min after administration. 35S in kidneys increased in a dose-dependent manner after administration of various doses of [35S]ZnMT, up to 1.3 mumole MT/kg; however, higher doses did not further increase renal 35S concentrations. A similar saturation of 35S reabsorption was observed for the renal uptake of [35S]CdMT. CdMT produced renal injury with doses as low as 0.26 mumol MT/kg (0.2 mg Cd/kg). In contrast, with a dose of ZnMT as high as 5.12 mumol MT/kg (2 mg Zn/kg), no histopathological changes were observed. Therefore, ZnMT appears to be nontoxic even though ZnMT delivers more MT to the kidney than does CdMT. Because ZnMT and CdMT are apparently handled by the same renal transport mechanism, the effects of ZnMT on 109CdMT renal uptake and nephrotoxicity were determined. One group of mice was given a nephrotoxic dose of 109CdMT (0.51 mumol MT/kg containing 0.4 mg Cd/kg, i.v.), and the other group received an equimolar dose of unlabeled ZnMT 1 min before 109CdMT administration. Renal function was evaluated by measuring urinary glucose and protein excretion, as well as histopathology.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cadmium; Dose-Response Relationship, Drug; Kidney; Kidney Diseases; Liver; Male; Metallothionein; Mice; Rats; Zinc

Interleukin-6 (IL-6) is a pleiotropic cytokine that has been postulated as playing a role in the pathogenesis of multiple myeloma, chronic autoimmune diseases, and alcoholic liver cirrhosis. We generated transgenic mice carrying a fusion between the mouse metallothionein-I (MT-I) gene promoter and the human IL-6 cDNA. MT-I/IL-6 transgenics express IL-6 constitutively in the liver and secrete the cytokine in the blood. They show initially activation of acute-phase response genes and accumulation of alpha 2- and beta-globulins in the plasma, which is followed by polyclonal hypergammaglobulinemia. MT-I/IL-6 transgenics die between 12 to 20 weeks of age. Histologic examination of transgenic animals at different ages and after necropsy showed, as expected from previous studies of IL-6 disregulation in vivo, an increase in the number of megakaryocytes in the spleen and bone marrow and, at later stages, IgG plasmacytosis in the spleen, lymph nodes, and thymus. However, no plasma cell infiltration was detected in other organs. The distinguishing feature of MT-I/IL-6 transgenics is the development of a progressive kidney pathology, in which the initial membranous glomerulonephritis is followed by focal glomerulosclerosis and finally by extensive tubular damage that reproduces the damage observed in patients at terminal stages of multiple myeloma (myeloma kidney). The pathogenetic role of IL-6 overproduction and of the resulting serum protein overload in the kidney damage is discussed.

Topics: Acute-Phase Proteins; Animals; Gene Expression; Interleukin-6; Kidney; Kidney Diseases; Liver; Lung; Lymph Nodes; Metallothionein; Mice; Mice, Transgenic; Multiple Myeloma; Plasma Cells; Promoter Regions, Genetic; Recombinant Fusion Proteins; RNA, Messenger; Spleen

Nephrotoxic effects of cadmium exposure are well established in humans and experimental animals. An early manifestation of such toxicity is calciuria a few hours after injection of CdMT in rats. Protection against calciuria and other adverse effects such as proteinuria (occurring later) is offered by pretreatment with Cd, which effectively induces metallothionein synthesis. In the present experiment, one group of animals was given pretreatment with CdCl2 to induce metallothionein synthesis. The comparison group was left without pretreatment. The distribution of Cd from a normally nephrotoxic dose of 109CdMT was studied by gel chromatography in subcellular fractions of kidney cortex in both groups. In the pretreated animals, 109Cd in the plasma membrane and microsome fractions of renal cortical cells was mainly bound to metallothionein and other low molecular weight proteins at 4 hr. In nonpretreated animals the major part of 109Cd was bound to high molecular weight proteins. These findings indicate that membrane proteins may be important targets for Cd when inducing nephrotoxicity and that sequestering of Cd by metallothionein (and other low molecular weight proteins) may be a mechanism of protection.

Topics: Animals; Cadmium; Cadmium Chloride; Calcium; Chlorides; Kidney Cortex; Kidney Diseases; Male; Membrane Proteins; Metallothionein; Protein Binding; Rats; Rats, Wistar; Subcellular Fractions

Cadmium metallothionein (CdMT) was injected subcutaneously into obese hyperglycaemic Umeå ob/ob mice or their lean litter mates (normal mice) at doses of 0, 0.1 and 0.4 mg Cd/kg. Proteinuria and calciuria were induced in both types of mice, but in the ob/ob mice this condition developed at a lower dose of CdMT (0.1 mg Cd/kg) than in the normal mice (0.4 mg Cd/kg). These results show, therefore, that Umeå ob/ob mice are particularly susceptible to CdMT-induced nephrotoxicity. The mechanism underlying this phenomenon needs to be further investigated. After the administration of CdMT, a dose-related increase in glycosuria was observed in both types of mice, in spite of decreased levels of serum insulin and glucose. It is suggested that such glycosuria induced by CdMT could be one of the signs of cadmium nephrotoxicity. The results of the present study thus indicate that metabolic changes like those in diabetes may increase susceptibility to cadmium-induced renal tubular damage.

Topics: Animals; Blood Glucose; Calcium; Diabetes Mellitus, Type 2; Disease Models, Animal; Dose-Response Relationship, Drug; Injections, Subcutaneous; Insulin; Kidney Diseases; Kidney Tubules; Liver; Male; Metallothionein; Mice; Mice, Obese; Obesity; Pancreas; Proteinuria; Tissue Distribution

Two epidemiological studies aimed at investigating the dose-response relationship of environmental cadmium exposure were performed in a population living in the Kakehashi River basin, a cadmium-polluted area in Japan. In the first, the average cadmium concentration in rice from each village was used as an indicator of exposure and metallothioneinuria or beta 2-microglobulinuria as an index of renal tubular dysfunction. Dose-related increases in both the latter indices were observed. The total cadmium intake resulting in both metallothioneinuria and beta 2-microglobulinuria was calculated to be approximately 2 g for both sexes. In the second study, the dose-response relationship between urinary cadmium and metallothioneinuria or beta 2-microglobulinuria was evaluated in the same population. Prevalence rates increased proportionally with increasing urinary cadmium (Cd-U). The values of Cd-U corresponding to the prevalence rates of metallothioneinuria in the non-exposed population were calculated to be 4.2 micrograms/g creatinine for men and 4.8 micrograms/g creatinine for women; for beta 2-microglobulinuria the corresponding figures were 3.8 micrograms/g creatinine for men and 4.1 micrograms/g creatinine for women.

Topics: Aged; beta 2-Microglobulin; Cadmium; Cadmium Poisoning; Dose-Response Relationship, Drug; Female; Food Contamination; Humans; Japan; Kidney Diseases; Kidney Tubules; Male; Maximum Allowable Concentration; Metallothionein; Middle Aged; Oryza

One group of male Wistar rats (Group B) was pretreated by a daily subcutaneous injection with CdCl2 during 5 days with increasing doses (0.5, 1, 1, 2 and 2 mg Cd/kg). Another group of rats (Group A) was daily given normal saline subcutaneously for 5 days. On the second day after the last injection, a single s.c. injection of 109Cd-metallothionein (CdMT, 0.4 mg Cd/kg) was given to each animal in both groups. Urinary calcium, protein, metallothionein (MT), N-acetyl-beta-D-glucosaminidase (NAG) and gamma glutamyltransferase (gamma-GT) were measured. In Group A, calciuria, proteinuria, metallothioneinuria and enzymuria was induced by CdMT. Calciuria reached a peak during 0-6 h after the administration of CdMT, thus appearing earlier than other effects. Enzymuria was displayed at 6-12 h for gamma-GT and 12-24 h for NAG. A prominent increase of proteinuria appeared at 24-48 h after the challenge of CdMT. In Group B, no significant increase of urinary calcium, protein, or NAG was observed after the CdMT injection and urinary gamma-GT was only slightly elevated, thus demonstrating the protective action of pretreatment. This study demonstrates for the first time that calciuria, one of the signs of cadmium nephrotoxicity, can be prevented by cadmium pretreatment. Urinary MT increased slightly during the 4-5 days of CdCl2 pretreatment. This is in accordance with previous observations that cadmium pretreatment induces new synthesis of MT which is likely to constitute the background for the resistance to the CdMT challenge to the kidney.

Topics: Acetylglucosaminidase; Animals; Cadmium; Cadmium Chloride; Calcium; Chlorides; gamma-Glutamyltransferase; Kidney Diseases; Kidney Tubules; Male; Metallothionein; Nephrons; Proteinuria; Rats; Rats, Wistar; Time Factors

Chronic, but not acute, exposure to inorganic Cd produces renal damage. However, a single injection of cadmium bound to metallothionein (CdMT) produces renal injury. It is hypothesized that an interorgan redistribution of Cd as CdMT is responsible for the chronic nephrotoxic effect of Cd. To better understand the mechanism(s) of CdMT-induced nephrotoxicity, the intrarenal distribution of 109CdMT was examined. 109CdMT isolated from rat liver was injected into mice at a nonnephrotoxic dose (0.1 mg Cd/kg, iv). The radioactivity in the kidney reached a maximum level (85% of the dose) as early as 30 min following administration and remained essentially constant for up to 7 days after injection. Within the kidney, 109Cd distributed almost entirely to the cortex. Light microscopic autoradiography of the kidney showed that, within the cortex, 109Cd distributed preferentially to the S1 and S2 segments of the proximal convoluted tubules. Within the S1 and S2 segments, the concentration of 109Cd in the basal and apical parts of the cells was similar to that after the nonnephrotoxic dose of CdMT, but after a nephrotoxic dose (0.3 mg Cd/kg) the radioactivity distributed preferentially to the apical portion of the cells. In contrast, light microscopic autoradiography studies with 109CdCl2 revealed that 109Cd was more evenly distributed throughout the proximal tubules. Moreover, after administration of a large dose of inorganic Cd (3 mg Cd/kg), a similar concentration of Cd was found in the convoluted and straight proximal tubules. These data support the hypothesis that CdMT-induced nephrotoxicity might be due, at least in part, to its preferential uptake of CdMT into the S1 and S2 segments of the proximal tubules, the site of Cd-induced nephrotoxicity.

Topics: Animals; Autoradiography; Cacodylic Acid; Cadmium; Cadmium Chloride; Cadmium Radioisotopes; Chlorides; Glutaral; Kidney; Kidney Diseases; Kidney Tubules, Proximal; Male; Metallothionein; Microscopy; Nephrons; Rats; Rats, Inbred Strains; Tissue Distribution

Factorial experimental design was used to study the protective effects of Zn and Cu on cadmium-metallothionein(CdMT)-induced nephrotoxicity in male Wistar rats. In the factorial design two levels of Zn (0 and 25 mg/kg body weight), two levels of Cu (0 and 12.5 mg/kg), and two levels of CdMT (0.1 and 0.4 mg of Cd/kg) were used as varied factors. The factorial design was complemented with a center point with all three variables at an intermediate setting, i.e., Zn at 12.5 mg/kg, Cu at 6.25 mg/kg, and CdMT at 0.25 mg Cd/kg. Each of the nine combinations of settings was administered to one of nine groups with six rats in each. Zn and Cu were injected sc 24 hr prior to the injection of CdMT. The concentrations of protein and Ca in urine and Ca in renal cortex were used as effects. The relationship between the experimental design settings and the effects were modeled with multiple regression. The multiple regression analysis revealed that for the high dose of CdMT (i) the enhanced values of protein in urine caused by CdMT injection could be more efficiently reduced by Zn than by Cu, and (ii) excessive Ca in urine and renal cortex could be more efficiently reduced by Cu than by Zn. No significant synergism or antagonism between Cu and Zn was found. These models can be used to estimate the dose levels of Zn and Cu which will reduce the toxic effects of CdMT. The treatment of 20.4 mg/kg Zn, for example, will reduce the effects of 0.4 mg Cd/kg as CdMT on protein in urine, and 2.8 mg/kg Cu will reduce the Ca in urine to the levels of those caused by 0.25 mg Cd/kg (no Zn and Cu). Similarly, the effect of 0.4 mg Cd/kg on Ca level in renal cortex can be reduced to that of 0.28 mg Cd/kg as CdMT by 7.98 mg Cu/kg, which is three times as efficient as Zn. The obtained results might be of importance in understanding the mechanism of cadmium toxicity and the potential risk to the health of the population exposed to cadmium occupationally or environmentally.

Topics: Animals; Cadmium; Calcium; Copper; Kidney Cortex; Kidney Diseases; Male; Mathematical Computing; Metallothionein; Models, Biological; Multivariate Analysis; Proteinuria; Rats; Rats, Inbred Strains; Regression Analysis; Zinc

Nephrotoxicity induced by cisplatin (CDDP) was reported to be reduced by Bi3(+)-pretreatment, which selectively induces renal metallothionein (MT). In the present study renal MT had increased to 250% of control in rats that received bismuth subnitrate (50 mumol/kg/day, orally) for 8 days. In vitro experiments demonstrated that the reduction of CDDP-induced toxicity is a renal effect: in proximal tubular cells (PTC) isolated from Bi3(+)-treated rats the toxicity of CDDP, and also of HgCl2, CdCl2 and p-aminophenol, was reduced as compared to PTC from untreated rats. In contrast to the reduction in CDDP, Hg2+ and Cd2+ toxicity, the reduction in p-aminophenol toxicity cannot be explained by the metal-binding properties of MT. MT was reported to act as a free radical scavenger, which may explain our observation since p-aminophenol toxicity is thought to be a consequence of the generation of oxygen radicals. In vivo experiments showed that the overall renal Pt-content as well as the Pt bound to renal MT is lower in Bi3(+)-pretreated rats than in untreated rats, 24 hr after administration of CDDP (12 mg/kg), suggesting that the reduction in nephrotoxicity is not due to increased binding of Pt2+ to renal MT. Renal superoxide dismutase (SOD) activity was increased in rats that had only received CDDP. Such a rise in SOD may result from peroxidative damage caused by exposure to CDDP. The fact that SOD was not elevated in rats that received Bi3+ prior to CDDP suggests that (i) peroxidation contributes to CDDP-induced nephrotoxicity and (ii) the anti-oxidant properties of MT are responsible for the reduction of this toxicity.

Topics: Animals; Antioxidants; Bismuth; Cisplatin; Cytosol; Drug Evaluation, Preclinical; Glutathione; Kidney Diseases; Kidney Tubules, Proximal; Male; Metallothionein; Rats; Rats, Inbred Strains; Superoxide Dismutase

An epidemiological study to evaluate cadmium-induced renal dysfunction by urinary metallothionein levels was carried out in an environmentally-exposed Japanese population. The study population consisted of 3168 men and women from a cadmium-polluted area who were 50 years and older and 291 individuals from a non-polluted area. The mean metallothionein levels in urine of the control population were 138.2 +/- 2.1 and 198.6 +/- 1.9 microgram/g creatinine for men and women, respectively. The corresponding values for the cadmium-exposed population were 157.8 +/- 2.2 and 248.0 +/- 2.2. The 97.5% upper limits for men in the control population was determined to be 638 and for women 693 microgram MT/g creatinine. Based on these values as the cut-off levels, the prevalence of metallothioneinuria was calculated to be 4.6% in men and 8.4% in women from the cadmium-polluted area. Further selection of the population, based on life-time residence in the polluted area accompanied with the consumption of cadmium-containing rice, showed an even greater prevalence of metallothioneinuria: 5.4% in men and 10.9% in women of all ages. The prevalence of metallothioneinuria increased with age and duration of residence in the polluted area. These results suggest that metallothioneinuria can be used as an indicator of renal dysfunction due to environmental cadmium exposure.

Topics: Age Factors; Aged; Aged, 80 and over; Cadmium; Creatinine; Environmental Exposure; Environmental Pollution; Female; Humans; Japan; Kidney Diseases; Male; Metallothionein; Middle Aged; Oryza; Prevalence; Sex Factors

To examine the combined hepatotoxic and nephrotoxic effects of cadmium and ethanol, rats maintained on an ethanol containing liquid diet (5% w/w) were given cadmium either acutely (3 x 1 mg/kg IP) or subacutely (about 14 mg/kg/day PO for 6 weeks). Parameters tested were cadmium, zinc and copper contents of blood and various organs, metallothionein (MT) contents, polysome profile of liver and kidneys, serum SDH and GPT levels and creatinine clearance. Ethanol reduced the hepatic MT contents without altering the polysome profile and the zinc and copper contents. Cadmium on the other hand raised the MT contents in liver and kidneys. This effect of cadmium predominated in the combined treatment. Morphological examination and functional tests (SDH, GPT, creatinine clearance) indicate that cadmium does not enhance the toxic effects of ethanol, and vice versa.

Topics: Alanine Transaminase; Animals; Body Weight; Brain Chemistry; Cadmium; Chemical and Drug Induced Liver Injury; Copper; Creatinine; Ethanol; Female; Kidney Diseases; L-Iditol 2-Dehydrogenase; Metallothionein; Organ Size; Polyribosomes; Protein Biosynthesis; Rats; Rats, Inbred Strains; Zinc

The effect of N-benzyl-D-glucamine dithiocarbamate (BGD) on the renal toxicity induced by acute exposure to cadmium-metallothionein (Cd-MT) in rats was studied. Rats were injected intraperitoneally with BGD (400 mumol/kg) 6, 12, or 24 h after intraperitoneal injection of Cd-MT (1.78 mumol Cd as Cd-MT/kg) and thereafter they received three injections of BGD (400 mumol/kg) daily for 3 days. Urinary protein concentration and aspartate aminotransferase (AST) activity significantly increased 1 day after Cd-MT treatment and decreased to control levels at 9 days after the treatment. Urinary excretion of glucose and amino acids rose gradually reaching maximum levels 5 days after Cd-MT treatment and returned to the control levels at 9 days. BGD injection significantly reduced the increases in the urinary excretion of protein, AST, glucose and amino acid, which were produced by Cd-MT treatment. Significant increases in urine volume were observed after Cd-MT treatment. BGD injection inhibited the increase in urine volume caused by Cd-MT treatment. A long time interval (12 and 24 h) between the administrations of Cd-MT and BGD resulted in a decreased protective effect of BGD against Cd-MT-induced renal damage. Following Cd-MT injection, the major route of excretion of cadmium (Cd) was via the urine and the kidney was the major site of accumulation of Cd. BGD injection remarkably increased the urinary excretion of Cd, resulting in a significant reduction in the kidney Cd concentration. The results of this study indicate that BGD injection is effective in decreasing the Cd concentration in the kidney, resulting in the protective effect on Cd-MT-induced renal damage.

Topics: Amino Acids; Animals; Aspartate Aminotransferases; Bile; Cadmium; Chelating Agents; Glycosuria; Kidney; Kidney Diseases; Liver; Male; Metallothionein; Proteinuria; Rats; Rats, Inbred Strains; Sorbitol; Thiocarbamates; Tissue Distribution

It has previously been reported that cadmium (Cd) induces renal lesions only after sequestration by endogenous metallothionein (MT), and not in the form of simple salts. However, in this report we detail findings of acute CdCl2-induced renal lesions in the Syrian hamster, which appear to be species specific as neither rats nor mice showed such lesions. Adult rats and mice of different strains and Syrian hamsters (Cr:RGH) were given Cd doses ranging from 30-50 mumol/kg, sc, and examined histologically for renal lesions between 2 hr and 7 days later. Hamsters developed necrosis of the proximal renal tubules 12-24 hr after CdCl2 treatment at an average incidence of 60% in both sexes. Tubular regeneration occurred within 1 week as shown by immunocytochemical localization of DNA synthesis with 5-bromo-2'-deoxyuridine. By electron microscopy, initial changes with Cd (16 hr) included cytoplasmic vesiculation and dilatation of endoplasmic reticulum, and swelling of mitochondria followed rapidly by enlargement of vacuoles, nuclear changes, and cellular disintegration. Rats and mice showed no such lesions even at lethal doses of Cd (40-50 mumol/kg). At maximum tolerated doses of Cd (approximately LD 10: for rats and mice, 35 mumol/kg; for hamsters, 50 mumol/kg) renal Cd content was not higher in hamsters than in the other species 24 hr after injection; hamsters, in fact, had the lowest Cd content. Likewise, basal or Cd-induced levels of renal MT were not remarkably different between these species. These results indicate the hamster is uniquely susceptible to acute effects of Cd on the kidney and that this effect is not related to an unusually high concentration of CdCl2 or unusually low basal or induced levels of MT in the kidney.

Topics: Animals; Cadmium; Cadmium Chloride; Cricetinae; Kidney; Kidney Diseases; Kidney Tubular Necrosis, Acute; Mesocricetus; Metallothionein; Mice; Mice, Inbred Strains; Microscopy, Electron; Rats; Rats, Inbred F344

The relationship between urinary metallothionein and kidney and liver cadmium levels was examined in 68 active and retired smelter workers. Metallothionein was analyzed by a radioimmunoassay and liver and kidney cadmium levels were determined by in vivo neutron activation. Four workers suffered from severe renal dysfunction and excreted high amounts of total protein and beta 2-microglobulin and greater than 1 mg metallothionein/g creatinine. In the remaining 64 workers the urinary metallothionein levels correlated significantly with the cadmium levels in both liver and kidney. Similarly, in these individuals urinary metallothionein was significantly related to cadmium in blood and urine. These results demonstrate that urinary metallothionein is a sensitive biological indicator of cadmium exposure and body burden, before the onset of severe renal dysfunction.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Body Burden; Cadmium; Environmental Exposure; Environmental Monitoring; Humans; Kidney; Kidney Diseases; Liver; Male; Metallothionein; Middle Aged; Neutron Activation Analysis; Radioimmunoassay; Regression Analysis

Renal functions were damaged at the reabsorptive site by the injection of cadmium-metallothionein (Cd-MT) and its effect on discrimination of chemically similar elements was examined for the two alkaline-earth elements, calcium (Ca) and strontium (Sr). Tubular damage was induced in female Wistar rats, 7 wk old, body wt 145.1 +/- 3.5 g (mean +/- S.D.), by an intraperitoneal injection of Cd-MT (400 micrograms Cd/kg body wt). The Cd-MT injection caused increases in urinary enzymes (lactate dehydrogenase; alkaline phosphatase), glucose, and total protein. Urinary Ca and Sr increased and urinary Sr/Ca ratio decreased rapidly after the Cd-MT injection. Both changes remained at significant levels throughout the experiment. On the other hand, renal Ca and Sr levels increased with time after 18 or 24 h and changed similarly. Although plasma levels of Ca and Sr slightly increased after 30 or 36 h post-injections, the plasma Sr/Ca level remained constant. A close exponential relationship formed between the relative clearances of Ca and Sr. There was no significant difference between the exponent of the following equation (K) for the Cd-MT-injected group and that for the control group. Sr clearance/creatinine clearance = (Ca clearance/creatinine clearance)K where K = 0.408 from experimental data for the two groups. This suggests that the discrimination mechanism between Sr and Ca during the reabsorptive step in the kidney is strictly regulated.

Topics: Alkaline Phosphatase; Animals; Calcium; Female; Glycosuria; In Vitro Techniques; Kidney; Kidney Diseases; L-Lactate Dehydrogenase; Male; Metallothionein; Proteinuria; Rats; Rats, Inbred Strains; Strontium

Male rats were injected SC with 0.6 mg Cd/kg/day for 5 days per week for 2, 4, 6, and 8 weeks. Liver and kidney were examined morphologically and analyzed for metallothionein, cadmium, zinc, and copper. Morphologic changes were found in kidney but not in liver. The earliest ultrastructural change consisted of myelin figures in vacuoles in cytoplasm of proximal tubular lining cells reflecting degeneration of membranes. This change occurred after 4 weeks with 801 +/- 25 nmol/g (89.9 micrograms/g) total kidney cadmium or 390 nmol/g (43.7 micrograms/g) of cadmium not bound to metallothionein. Similar changes were observed after 6 weeks but after 8 weeks pathological changes consisted of focal cellular necrosis and interstitial fibrosis. Other ultrastructural changes included altered mitochondria and increased numbers of microbodies. Renal cadmium after 8 weeks exposure was 1827 +/- 48 nmol/g (215.3 +/- 5.8 micrograms/g) or 628 nmol/g (70.2 micrograms/g) of cadmium not bound to metallothionein. Total cadmium was higher in liver than in kidney but partitioning between bound and nonbound cadmium differed in the two organs. The fraction not bound to metallothionein increased with time of exposure in both liver and kidney. However, total cadmium in the liver did not exceed potentially available binding sites of metallothionein, whereas total cadmium did exceed potentially available binding sites of metallothionein in the kidney where pathologic changes occurred. The results indicated that degeneration of cellular membranes is an early cellular effect of cadmium exposure followed later by toxicity to organelles, cellular necrosis, and interstitial fibrosis. Cadmium-induced cellular toxicity is more directly related to the fraction of cadmium in the kidney that is not bound to metallothionein than is total cadmium per se.

Topics: Animals; Cadmium; Copper; Dose-Response Relationship, Drug; Kidney Cortex; Kidney Diseases; Kidney Tubules, Proximal; Liver; Male; Metallothionein; Microscopy, Electron; Rats; Rats, Inbred Strains; Zinc

This report describes the metallothionein (MT) levels and accumulation of mercury, lead, and cadmium, as well as their interaction with tissue zinc, copper, and iron, and the histopathological changes in kidneys of ducks exposed to methylmercury chloride (MeHgCl), lead acetate (PbAc), and cadmium chloride (CdCl2), singly or in combination for 13 wk. Forty-eight female Pekin ducks, divided into 8 groups of 6 birds each, were fed diets containing no added metals (control), 8 mg MeHgCl/kg feed, 80 mg PbAc/kg feed, 80 mg CdCl2/kg feed, 8 mg MeHgCl + 80 mg PbAc/kg feed, 8 mg MeHgCl + 80 mg CdCL2/kg feed, 80 mg PbAc + 80 mg CdCl2/kg feed, and 8 mg MeHgCl + 80 mg PbAc + 80 mg CdCL2/kg feed. Cadmium (Cd) when administered alone or in combination caused a 60-fold increase in kidney MT levels, while methylmercury (MeHg) or lead (Pb) administration caused a threefold increase in kidney MT levels. No significant changes in kidney MT levels were observed when metals were administered concurrently when compared with single-treatment groups. Residue analysis revealed accumulation of administered metals in kidney tissue. However, lead administration resulted in accumulation of small amounts of this element in kidney tissue. Simultaneous administration of MeHgCl and PbAc significantly increased the accumulation of lead in kidney when compared with PbAc-treated group. Cadmium when administered alone or in combination caused an increase in the levels of zinc and copper in kidney. Administration of MeHgCl or PbAc either alone or in combination caused increased iron levels in kidney, while cadmium administration either alone or in combination caused decreased iron levels. Administration of cadmium either alone or in combination caused degenerative changes in kidney proximal tubules. The severity of degenerative lesions increased when cadmium was simultaneously administered with other metals. These results indicate that combined administration of MeHg, Pb, and Cd has no significant effect on kidney MT levels or on essential elements in kidney tissue when compared with single metal groups. However, there appears to be an increase in the severity of histopathologic changes.

Topics: Animals; Cadmium; Diet; Drug Interactions; Ducks; Female; Kidney Cortex; Kidney Diseases; Kidney Tubules, Collecting; Kidney Tubules, Proximal; Lead; Metallothionein; Methylmercury Compounds; Tissue Distribution; Trace Elements

An epidemiologic investigation was carried out to study the significance of urinary excretion of metallothionein (MT) in people aged 50 years and over living in a cadmium (Cd)-polluted area in Japan. The urinary level of MT was compared with various parameters (age, urinary alpha 1-microglobulin (alpha 1-MG), beta 2-microglobulin (beta 2-MG), total protein, Cd, copper (Cu), and zinc (Zn), and relative clearances to creatinine of alpha 1-MG, beta 2-MG, phosphate and uric acid). It was found that the urinary excretion of MT is closely associated with Cd and the indices of renal dysfunction listed above. This observation was more remarkable in women than men. When subjects with signs of renal dysfunction were compared as a group to those with normal renal functions, the excreted amount of MT in the former is significantly greater. The results support the notion that the urinary excretion of MT reflects not only Cd exposure levels but also renal dysfunction caused by long-term Cd exposure.

Topics: Acetylglucosaminidase; Aged; Aged, 80 and over; Aging; Alpha-Globulins; beta 2-Microglobulin; Cadmium Poisoning; Environmental Pollutants; Female; Humans; Japan; Kidney Diseases; Male; Metallothionein; Metals; Middle Aged

Pretreatment with Na2MoO4 protected rats from HgCl2-induced decreases in the renal concentration of amino acids, RNA, DNA, ATP and dry matter. It also reduced the mercury-induced increases in renal water, Ca and serum creatinine. Ma2MoO4 considerably elevated the RNA/DNA ratio in the renal cortex after treatment with HgCl2. In addition, subcellular distribution of mercury was markedly altered by pretreatment with Na2MoO4, specifically Na2MoO4 pretreatment decreased the mercury content in the particulate fractions such as the nuclei and mitochondria while increasing the mercury content of the cytosol. Sephadex G-75 gel filtration showed that the increase in mercury content in the cytosol of Na2MoO4-pretreated rats is due to an increase in the metal content of a metallothionein-like fraction. These results suggest that Na2MoO4-pretreatment protects against HgCl2 renal toxicity by stimulating mercury-mediated metallothionein induction in the renal cortex and renal regenerative processes.

Topics: Adenosine Triphosphate; Animals; Cations; Creatine; DNA; gamma-Glutamyltransferase; Kidney; Kidney Diseases; Mercury; Mercury Poisoning; Metallothionein; Molybdenum; Rats; Regeneration; RNA; Water

The nephrotoxicity of Cd-metallothionein (Cd-MT) was examined after iv administration of various dosages to mice. The lowest dosage of Cd-MT that produced renal injury was 0.2 mg Cd/kg. This dosage of Cd-MT resulted in 10 micrograms Cd/g in the kidneys 24 hr after administration. A time-course experiment utilizing a higher (0.3 mg Cd/kg) nephrotoxic dose of Cd-MT demonstrated that the renal Cd concentration at 4 and 12 hr was much higher than the critical concentration, but thereafter decreased to about 10 micrograms Cd/g wet tissue by 24 hr. Thus, Cd in excess of 10 micrograms/g appears to damage the kidney and then distributes to other tissues and/or is excreted into urine. When a total of 0.3, 0.4, and 0.8 mg of Cd/kg as Cd-MT was administered in divided dosages over 4 days, as much as 30 micrograms Cd/g was detected in the kidney but no renal injury was observed. Thus, the critical concentration for producing renal injury after acute administration of Cd-MT is estimated to be approximately 10 micrograms Cd/g wet weight. However, with repeated exposure to Cd-MT, this acute critical concentration can be exceeded without producing renal injury, as tolerance to the nephrotoxic effects of Cd-MT develops.

Topics: Animals; Cadmium; Injections, Intravenous; Kidney; Kidney Diseases; Kidney Function Tests; Liver; Male; Metallothionein; Mice; Organ Size; Rats; Rats, Inbred Strains

Prolonged cadmium exposure has been associated with proteinuria, calcuria and loss of calcium from bones in humans. Previous studies have shown that kidney uptake of cadmium in vivo results from proximal tubule absorption of the circulating cadmium metallothionein complex (CdMT), and intracellular release of the Cd2+ ion prior to induction of renal metallothionein. Parenteral administration of CdMT has been found to selectively damage the proximal tubule cell lysosome system with development of a tubular proteinuria pattern similar to that observed under chronic exposure conditions. The present studies also demonstrate a concomitant calcuria but no changes in the excretion of other electrolytes or glucose using this model. These marked changes in renal calcium metabolism occurred in the absence of mitochondrial damage, changes in total, Na/K or Mg-stimulated ATPase activities, renal ATP levels, membrane 45Ca2+ transport or overt tubule cell necrosis during an 8 hour period following CdMT injection. Proteinuria and calcuria were prevented by prior zinc induction of the renal MT pool. Data from these studies indicate that renal proximal tubule cell uptake and degradation of the circulating CdMT complex produces both a marked proteinuria and calcuria. The calcuria does not appear to stem from changes in renal energy metabolism or membrane transport of this element but is probably a secondary result of calcium binding to excreted proteins which are increased in urine to a similar extent. The studies also suggest that zinc status and maintenance of the renal ZnMT pool may play an important role in regulating cadmium-induced renal proteinuria and calcuria by preventing Cd2+ perturbation of the proximal tubule cell lysosome system.

Topics: Adenosine Triphosphate; Animals; Biological Transport; Ca(2+) Mg(2+)-ATPase; Calcium; Cell Membrane; Kidney; Kidney Diseases; Kidney Tubules, Proximal; Lysosomes; Metallothionein; Mitochondria; Proteinuria; Rats; Sodium-Potassium-Exchanging ATPase; Zinc

The effect of preadministration of bismuth, a specific potent inducer of renal metallothionein (MT), on the lethal and renal toxicity of cis-DDP, an extensively used antitumor drug containing heavy metal platinum, in mice was investigated. Pretreatment of mice with two s.c. doses of bismuth nitrate (BN; 30 mumol/kg/day) at 24-hr interval prevented the lethal toxicity, the increase in BUN value and the occurrence of diarrhea caused by cis-DDP (35 mumol/kg, s.c.). This protective effect of BN-pretreatment was significantly correlated with increased MT levels in the kidney. The pretreatment of tumor-bearing mice with BN also depressed the lethal and renal toxicity of cis-DDP without compromising its antitumor activity, and allowed the administration of relatively high dose of cis-DDP. Daily five consecutive p.o. preadministration of bismuth subnitrate (BSN), one of the bismuth compounds being in use as a protectant of the gastrointestinal lining, was also effective to depress the lethal toxicity of cis-DDP. Since the effective dose of BSN is not far from that commonly used for men, this treatment will allow the increase in cis-DDP dose, promising a clinical advantage in cancer chemotherapy.

Topics: Adenocarcinoma; Animals; Bismuth; Cisplatin; Colonic Neoplasms; Kidney; Kidney Diseases; Metallothionein; Mice; Neoplasm Transplantation

Metallothionein plays an important role in the metabolism and toxicity of cadmium. Human beings are exposed to increasing amounts of cadmium. The critical organ in long term cadmium exposure is the kidney. Some groups in the population fall within the risk zone for developing renal tubular dysfunction from cadmium exposure. After absorption, cadmium is to a large extent distributed to the liver where it is bound to and induces the synthesis of metallothionein. Subsequently metallothionein-bound cadmium is slowly released into blood and efficiently taken up by renal tubular cells after glomerular filtration. The biological half-time of cadmium in the human kidney is considered to be very long: 10-15 years and this explains the life-long accumulation of cadmium, reaching a toxic concentration of approximately 200 ug/g in excessively exposed individuals. Human adult renal metallothionein has a natural content of cadmium which also induces the resynthesis of this protein upon its catabolism. This could be one explanation of the long biological half-time which has been reported for cadmium. Injection of metallothionein-bound cadmium can induce renal tubular kidney dysfunction at lower renal cadmium concentrations (10-20 ug/g), probably because of the fast catabolism and relatively slow synthesis of metallothionein in renal cells. A model of these and other mechanisms causing tubular kidney damage in cadmium exposure is presented.

Topics: Animals; Cadmium; Half-Life; Kidney; Kidney Diseases; Kidney Tubules; Metallothionein; Mice; Protein Binding; Serum Albumin; Tissue Distribution

Three groups of rats (B-D) were given various daily doses of CdCl2 (0.5-2 mg Cd/kg) continuously or in intervals during time periods of 1-8 weeks. Another group of animals (A) were kept untreated. At the end of the period, selected subgroups of groups A-D were given a single subcutaneous injection of 109Cd-metallothionein (109CdMT) 0.05 or 0.4 mg Cd/kg ("challenge dose"). Subsequently, urinary creatinine, protein, Cd, 109Cd and MT and kidney cortex Cd, 109Cd and MT were determined. In group A (no long term pretreatment), an increased proteinuria was observed after the rats had received the lower of the challenge doses of 109CdMT, and an even greater increase after the higher challenge dose of 109CdMT. No such increase appeared in group B, C and D (repeatedly pretreated with CdCl2) at either of the challenge doses. Higher metallothionein concentrations in kidney cortex observed in the pretreated groups constitute a plausible explanation of the protective effects of pretreatment against the development of increased proteinuria after challenge dosing. It is likely that increasing Cd concentrations, gradually accumulating in the renal cortex (22-226 micrograms/g wet wt.) as a result of the pretreatment, served to induce the synthesis of metallothionein in the renal cortical cells, thus making them resistant to the challenge from 109CdMT.

Topics: Acute Disease; Animals; Cadmium; Cadmium Chloride; Kidney Diseases; Male; Metallothionein; Proteinuria; Rats

To evaluate a critical concentration concept of cadmium (Cd) toxicity on the kidney, relationships of renal Cd level with urinary excretion of various substances--i.e., metallothionein, alkaline phosphatase, lactate dehydrogenase, N-acetyl-beta-D-glucosaminidase, total protein, Cd, copper, and zinc--were studied in Cd-injected rats. At the renal Cd concentration of 100-200 micrograms/g tissue, a dramatic increase of all these substances in urine was observed, supporting the idea of the critical concentration proposed by Friberg and co-workers (1974). The significance of increase of urinary metallothionein below this level is also discussed.

Topics: Acetylglucosaminidase; Alkaline Phosphatase; Animals; Cadmium; Copper; Dose-Response Relationship, Drug; Female; Kidney Diseases; L-Lactate Dehydrogenase; Metallothionein; Rats; Zinc

Rats were injected sc with 0.5 mg Cd/kg, 6 days/week, for up to 26 weeks. Hepatic and renal function and tissue Cd and metallothionein (MT) content were determined in tissues and plasma at various times after Cd injection. Cd in liver and kidney increased linearly for the first 10 weeks of treatment, but thereafter hepatic concentrations of Cd decreased by 33% whereas the content of Cd in kidney remained constant. MT in liver and kidney increased linearly during the first 12 weeks of Cd treatment to 4400 and 2300 micrograms MT/g, respectively, but rose only slightly thereafter. Circulating concentrations of MT progressively increased beginning 2 weeks after Cd treatment and were approximately 10 times control values in rats dosed with Cd for 12 or more weeks. Plasma activities of alanine and aspartate aminotransferase exhibited a time course similar to that observed with MT, and were elevated as early as the sixth week of Cd exposure. Sharp increases in activities of these enzymes also occurred after 10 to 12 weeks of dosing. Hepatic microsomal metabolism of benzo[a]pyrene and ethylmorphine was severely attenuated beginning 4 weeks after Cd. Renal injury occurred after hepatic damage, as evidenced by decreased in vitro p-aminohippuric acid uptake beginning 8 weeks after exposure. Urine outflow increased threefold 11 weeks after Cd exposure began, while urinary protein and Cd excretion increased beginning at Week 9. These data indicate the liver is a major target organ of chronic Cd poisoning, and suggest that Cd-induced hepatic injury, via release of Cd-MT, may play an important role in the nephrotoxicity observed in response to long-term exposure to Cd.

Topics: Animals; Body Weight; Cadmium; Cadmium Poisoning; Chemical and Drug Induced Liver Injury; Kidney; Kidney Diseases; Liver; Liver Diseases; Male; Metallothionein; Organ Size; Rats; Rats, Inbred Strains; Tissue Distribution

Evaluation of the potential adverse human health effects of low-level chronic exposure to heavy metals is dependent on the basic knowledge of the cellular and molecular toxicology of these metals. The use of various cell culture systems has greatly facilitated our knowledge of the cellular effects. Inasmuch as most of the acute and chronic toxic effects of metals occur primarily on the renal proximal tubules, the development of a rat kidney epithelial cell culture has provided a unique system to study the uptake and mechanism of toxicity of metals and their intracellular binding ligands. In the presence of D-valine, fibroblast growth was retarded and a primary epithelial monolayer culture was selectively grown from rat kidney cells. A distinct difference in the uptake of chemically similar divalent metals, such as Pb2+, Hg2+, Cd2+, and Zn2+, was observed in these cells. Both Pb2+ and Hg2+ were more avidly taken up by kidney cells than Cd2+ and Zn2+ salts and they also showed increased toxicity. On the other hand, the cellular uptake of Cd from cadmium-metallothionein (CdMT) was much less than from CdCl2, but CdMT was about seven times more toxic than CdCl2 when added to the renal cell culture. The cytotoxicity of CdCl2 was decreased significantly with pretreatment of the cells with CdCl2, although this had no effect on the toxicity of CdMT. The cellular toxicity of CdMT occurred probably during the process of its transport across the plasma membrane whereas that of CdCl2 occurred after it had entered the cell. Thus rat kidney epithelial cells may be a useful tool to study the mechanism of renal toxicity of environmental chemicals and drugs.

Topics: Animals; Cadmium; Cell Survival; Cells, Cultured; Culture Media; Diffusion; Epithelium; Kidney Diseases; Kidney Tubules, Proximal; Lead; Mercury; Metallothionein; Metals; Rats; Zinc

The critical concentration of cadmium (Cd) in the kidney after acute administration of Cd-cysteine (Cys) is 10 micrograms/g wet wt in whole kidney and is equal to that following Cd-thionein (Th) injection. This fact suggests that the nephrotoxicity of Cd-Th may be due to the Cd ions liberated from Cd-Th. To clarify the mechanism of the nephrotoxicity, the subcellular distribution of Cd injected as Cd-Cys was determined between supernatant and sediment fractions. Renal Cd level observed at 4 h increased with dose, but the Cd concentration in the supernatant fraction was kept almost constant at higher doses. Renal dysfunction measured by urinary protein and glucose levels was seen at the higher doses. This suggested that Cd in the sediment fraction of the kidney homogenates may be the ultimate cause for the nephrotoxicity of Cd-Cys. The sedimental Cd was eliminated from the kidney by 24 h. Much of the Cd found in the supernatant fraction was bound to high-molecular-weight proteins (HMWP) at 4 h, and almost all Cd ions were found to be bound to metallothionein at 24 h. Therefore, the HMWP-bound Cd in the supernatant fraction also may be a cause for the renal dysfunction. It is concluded that in addition to the HMWP-bound Cd in the supernatant fraction, CD distribution into the sediment fraction should be considered as a factor in causing nephrotoxicity after Cd-Cys and possibly Cd-Th administration.

Topics: Animals; Cadmium; Chromatography, High Pressure Liquid; Creatinine; Cysteine; Glucose; Injections, Intravenous; Kidney; Kidney Diseases; Liver; Male; Metallothionein; Mice; Mice, Inbred ICR; Proteins; Tissue Distribution

Rats were injected daily, five days/week, with 0.6 mg Cd/kg as CdCl2 for eight weeks. Groups of rats were sacrificed weekly. Urine, plasma and tissue cadmium levels, and morphology of renal cortex were studied. No abnormal effects were found until the fifth or sixth week when cadmium in kidney reached about 100 micrograms/g tissue. At this time, renal tubular lining cells showed an increase in lysosomes, microbodies and smooth endoplasmic reticulum and a low molecular weight cadmium-binding species was detectable in plasma. These changes were followed by the onset of glycosuria and proteinuria, accompanied by abnormal mitochondrial morphology. This progressed to cellular swelling and finally necrosis at the seventh and eighth weeks when cadmium concentration of the kidney reached about 200 micrograms/g of tissue. It is concluded that there are two phases in the development of cadmium induced nephropathy. Phase I is an adaptive phase characterized by some increase in smooth endoplasmic reticulum, microbodies and secondary lysosomes and the presence of metallothionein intracellularly in liver and kidney, but no detectable metallothionein in plasma and no increase in urinary cadmium. Phase II is a toxic phase characterized by detectable low molecular weight cadmium-binding species in plasma and evidence of renal tubular dysfunction followed by lethal injury to renal tubular lining cells.

Topics: Animals; Cadmium; Cadmium Poisoning; Kidney; Kidney Diseases; Liver; Male; Metabolic Clearance Rate; Metallothionein; Rats; Rats, Inbred Strains; Zinc

Topics: Animals; Cadmium; Cadmium Poisoning; Humans; Kidney; Kidney Diseases; Metallothionein

The paper is a review of certain aspects of importance of cadmium and the kidney regarding the assessment of risks and understanding of mechanisms of action. The review discusses the following topics: history and etiology of cadmium-induced kidney dysfunction and related disorders; cadmium metabolism, metallothionein and kidney dysfunction; cadmium in urine as indicator of body burden, exposure and kidney dysfunction; cadmium levels in kidney and liver as indicators of kidney dysfunction; characteristics of early kidney dysfunction; the critical concentration concept; critical concentrations of cadmium in kidney cortex; and prognosis.

Topics: Animals; Body Burden; Cadmium; Humans; Kidney; Kidney Diseases; Liver; Metallothionein; Prognosis

The relationship between metallothionein (MT), chronic exposure to cadmium (Cd), and renal function was investigated in 53 men who were occupationally exposed to Cd. The aim was to determine if MT is a potential biological monitor for chronic exposure to Cd which would be useful for preventing Cd nephropathy. In this study MT excretion, serum MT, and serum creatinine concentrations were significantly higher in subjects with abnormal renal function who had been exposed to Cd. MT excretion was also linearly related on an individual basis to protein excretion, beta 2-microglobulin (beta 2-M) excretion, and cumulative time weighted exposure (dose). MT excretion was also a better predictor of dose than either beta 2-M excretion or Cd excretion. The findings suggest that MT is a potential biological monitor for chronic Cd exposure that would be useful for preventing Cd-induced nephropathy. Further studies of non-specific nephropathies and MT are needed to determine if MT is a specific indicator of proximal tubule function secondary to chronic exposure to Cd.

Topics: Adult; beta 2-Microglobulin; Cadmium; Chemical Industry; Creatinine; Humans; Kidney Diseases; Male; Metalloproteins; Metallothionein; Metallurgy; Middle Aged; Occupational Medicine; Smoking; Time Factors

Cadmium in blood (Cd-B) and in urine (Cd-U) and metallothionein (Mt-U) and beta 2-microglobulin in urine (beta 2m-U) were measured in 94 male Cd workers. The results were examined according to the workers' current exposure to cadmium (group C, n = 73, workers currently exposed to Cd; group R, n = 21, Cd workers removed from exposure or retired) and according to their renal status (group N, n = 66, normal beta 2m-U; group I, n = 28, beta 2m-U greater than 200 micrograms/g creatinine). The interrelationships between Mt-U, Cd-U, Cd-B and years of cadmium exposure were examined in the various subgroups. The study of the correlations between these variables demonstrates that Mt-U is directly correlated with Cd-U but not with Cd-B or years of Cd exposure. The association between Cd-U and Mt-U is independent of the status of renal function and the intensity of current exposure to cadmium. Under moderate chronic exposure to cadmium, the fraction of Cd-U which is directly influenced by recent exposure (Cd-B) is small in comparison with that influenced by the cadmium body burden.

Topics: Adult; Aged; beta 2-Microglobulin; Cadmium; Cadmium Poisoning; Humans; Kidney Diseases; Male; Metallothionein; Middle Aged; Occupational Diseases; Time Factors

A single intravenous dose of 0.8 mg thionein-bound cadmium (Cd) per kg body weight, as the isolated (Cd, Zn)-metallothionein (MT) from rat liver, in rats of the same strain is nephrotoxic, but not lethal. Apical vesiculation in epithelial cells of the renal proximal convoluted tubules is apparent within 1 h of dosing and, by 4 h, is extensive in some of these cells that surround the larger arteries in the cortex. The membranes of these cells appear undamaged. The lesion at first progresses with time; by 24 h, the initially affected cells show extensive necrosis and most proximal convoluted tubular epithelia in other regions of the cortex are hydropically or vacuolarly degenerated. The inner stripe of the outer zone of the medulla and other portions of the nephron (glomerulus, distal tubule and collecting duct), however, appear essentially unaffected. The necrotic changes are maximal at 48 h but, after this time, regeneration begins. By seven days, much of the cell debris has been eliminated and cells of the regenerating or regenerated epithelia are similar in morphology to those of the normal kidney. Electron microscopic autoradiography of kidney sections from rats after administration of 109Cd-metallothionein of high specific activity shows that Cd is not concentrated in endocytotic vesicles, lysosomes, or any other cellular organelle, even at early times after dosing, but is distributed evenly throughout the epithelial cell. Thus, although Cd-MT appears to be taken up endocytotically in the kidney tubules, it appears that liberation of Cd from the metalloprotein must occur very early in the reabsorptive process.

Topics: Animals; Autoradiography; Cadmium; Female; Kidney; Kidney Diseases; Kidney Tubules, Proximal; Metallothionein; Microscopy, Electron; Rats; Rats, Inbred Strains; Regeneration

The significance of elevated excretion of metallothionein in urine of women living in cadmium-polluted areas of Japan was studied with respect to renal dysfunction. The relationships between the concentrations of metallothionein in urine and those of other non-specific urinary indices of renal dysfunction, i.e., total protein, glucose, beta 2-microglobulin, retinol-binding protein, alpha-amino nitrogen and proline were examined. In addition, the relationships between urinary metallothionein and urinary cadmium and copper were also evaluated. It was found that the logarithm of the metallothionein concentration in urine was significantly correlated with the logarithm of the concentrations of each of the above parameters. When subjects with signs of renal dysfunction, including "itai'itai" disease patients and patients suspected of the disease, were compared with subjects with normal renal functions, as a group, the former excreted significantly higher concentrations of metallothionein in their urine than the latter. The results suggest that the elevated excretion of metallothionein is not only an index of excessive cadmium exposure, but also of renal dysfunction caused by chronic exposure to this metal.

Topics: Aged; Cadmium Poisoning; Copper; Environmental Exposure; Female; Glycosuria; Humans; Kidney Diseases; Metalloproteins; Metallothionein; Middle Aged; Proteinuria

Metallothionein, a low molecular weight cadmium-binding protein, has been determined for the first time in urine of "itai-itai" disease patients and other Japanese women environmentally exposed to cadmium. On a group basis, the urinary metallothionein levels of "itai-itai" disease patients and suspected patients were significantly higher than that of women living in a cadmium-polluted area. Women living in a non-polluted area excreted significantly less metallothionein than women living in a cadmium-polluted area. A similar trend was observed for urinary beta 2-microglobulin, a nonspecific index of renal tubular dysfunction. However, mean levels of urinary cadmium in the "itai-itai" disease patients, suspected patients and women living in the cadmium-polluted area were similar. It is suggested that if, in addition to beta 2-microglobulin and cadmium, metallothionein is used as another index of cadmium exposure, monitoring of renal tubular dysfunction caused by cadmium may be more effectively carried out.

Topics: Aged; beta 2-Microglobulin; Cadmium; Cadmium Poisoning; Environmental Exposure; Female; Humans; Kidney Diseases; Metalloproteins; Metallothionein; Middle Aged

Repeated s.c. injections of cadmium chloride into rats (3 mg Cd/kg body weight, 4 times a week) caused acute and transitory tubular necrosis after 2 to 3 weeks; recovery was observed after 4 weeks despite continued loading. Kidney copper decreased for the first 3 weeks and was slightly increased after 4 weeks. Distribution profiles of cadmium (Cd), zinc (Zn), copper (Cu) on an SW column revealed that elution profiles of kidney metallothionein changed from typical kidney with high copper content to typical liver metallothioneins with tubular necrosis and restoration.

Topics: Animals; Cadmium; Cadmium Poisoning; Copper; Female; Kidney; Kidney Diseases; Metalloproteins; Metallothionein; Necrosis; Rats; Rats, Inbred Strains; Zinc

Topics: Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Enzymes; Kidney Diseases; L-Lactate Dehydrogenase; Male; Mercury; Metallothionein; Rats; Time Factors

Three different molecular weight cadmium-binding proteins isolated from the earthworm, Eisenia foetida, were injected intraperitoneally into young female rats. Cadmium bound to earthworm protein-I (estimated molecular weight, 63,000-70,000 daltons) and -II (estimated molecular weight about 7,000 daltons) was recovered from the kidney supernatants as metallothionein, which indicated that the proteins were degraded and that the cadmium liberated from the degraded proteins induced metallothionein biosynthesis in the kidneys. However, cadmium bound to earth-worm protein-III (estimated apparent molecular weight about 2,000 daltons) was recovered primarily from urine as a form bound to the protein. Compared with cadmium bound to albumin, metallothionein, and the low molecular weight cadmium-binding protein in Chlorella, the metabolic fates of cadmium bound to the three earthworm proteins were explained by the differences of molecular sizes and stability constants. Induced metallothioneins showed different chromatographic properties with time after injections on a Sephadex G-75 column and on a gel permeation column (TSK GEL SW 3,000).

Topics: Animals; Cadmium; Carrier Proteins; Glycosuria; In Vitro Techniques; Kidney Diseases; Liver; Metalloproteins; Metallothionein; Metals; Molecular Weight; Oligochaeta; Proteins; Rats

Topics: Animals; Kidney; Kidney Diseases; Male; Mercury; Mercury Poisoning; Metalloproteins; Metallothionein; Rats; Spironolactone; Zinc

Topics: Animals; Cadmium; Kidney; Kidney Diseases; Liver; Male; Metalloproteins; Metallothionein; Rats; Subcellular Fractions; Time Factors