Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
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Cadmium-metallothionein, mobilized from the liver, might be the toxic serum factor associated with pre-eclampsia. We base this on four documented concepts. First, during pregnancy, maternal physiology adjusts to assure the fetus of the proper amounts of nutrients necessary for growth. Our focus is on zinc and progesterone. Second, because zinc and cadmium are similar, they compete for binding sites. Our focus is on the storage protein metallothionein. Third, the manifestations of cadmium toxicity closely mimic the manifestations of toxemia (i.e. hypertension, proteinuria, edema). Our focus is on cadmium-induced endovasculitis. Fourth is the concept that metallothionein-bound cadmium can be mobilized from the liver into the serum during pregnancy as it follows the mobilization of metallothionein-bound zinc. Our focus is on the extreme toxicity of extracellular cadmium-metallothionein. We correlate these four concepts into a rational theory on the etiology of toxemia, and we suggest a method of proof.
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PMID:Further observations on the etiology of pre-eclampsia: mobilization of toxic cadmium-metallothionein into the serum during pregnancy. 886 28

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.
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PMID:Acute CdMT injection is not a good model to study chronic Cd nephropathy: comparison of chronic CdCl2 and CdMT exposure with acute CdMT injection in rats. 987 99

The sequence of structural changes terminating in glomerulosclerosis, tubular atrophy and interstitial fibrosis was analyzed in the growth hormone (GH) transgenic mouse (TM) model of progressive renal disease. The investigation was performed in TM expressing the bovine GH gene under the control of the murine metallothionein-1-promoter and non-transgenic controls (CM) of different age groups. The kidneys were studied by light microscopy, transmission and scanning electron microscopy, and were analyzed with stereological methods. Early-stage renal lesions were characterized by glomerular hypertrophy and mesangial expansion. In 7-week-old TM the mean glomerular volume was twice that of age-matched CM. The number of endothelial and of mesangial cells per glomerulus was increased in TM vs. CM, while the number of podocytes did not change. The podocytes demonstrated hypertrophy and foot process effacement. Concomitant with an age-related further increase of glomerular size in TM, severe maladaptive podocyte lesions including detachment of podocytes were observed. The resultant denudation of the glomerular basement membrane was associated with severe proteinuria, glomerular hyalinosis, synechia formation and collapse of glomerular capillaries. These lesions progressed to glomerular obsolescence that was associated with atrophy of the adjacent tubule and interstitial fibrosis. The progressive kidney lesions in this model appear to be attributable to a considerable extent to podocyte damage resulting from the limited capacity of this cell type to keep up with progressing overall tuft growth. The findings provide further evidence that mature podocytes are unable for effective cell replication in vivo, and that podocyte damage plays a significant role in the pathogenesis of progressive glomerulosclerosis with tubular atrophy and interstitial fibrosis.
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PMID:[Role of podocyte damage in the pathogenesis of glomerulosclerosis and tubulointerstitial lesions: findings in the growth hormone transgenic mouse model of progressive nephropathy]. 1189 6

Nephrotoxicity in humans and experimental animals due to chronic exposure to cadmium (Cd) is manifested by defects in the reabsorptive and secretory functions of proximal tubules (PT). The main symptoms of Cd nephrotoxicity, including polyuria, phosphaturia, aminoaciduria, glucosuria, and proteinuria, suggest that various brush-border membrane (BBM) transporters are the main targets of Cd. Specific transporters may be either directly inhibited by Cd or lost from the BBM after Cd treatment, or both. We have recently proposed that Cd may impair the vesicle-dependent recycling of BBM transporters by inhibiting vacuolar H+-ATPase (V-ATPase) activity and endocytosis in PT cells (Herak-Kramberger CM, Sabolic I, and Brown D. Kidney Int 53: 1713-1726, 1998). The mechanism underlying the Cd effect was further explored in an in vivo model of experimental Cd nephrotoxicity induced by Cd-metallothionein (Cd-MT; 0.4 mg Cd/kg body mass; a single dose sc) in rats. The time-dependent redistribution of various BBM transporters was examined in this model by fluorescence and gold-labeling immunocytochemistry on tissue sections and by immunoblotting of isolated renal cortical BBM. In PT cells of Cd-MT-treated rats, we observed 1) shortening and loss of microvilli; 2) time-dependent loss of megalin, V-ATPase, aquaporin-1 (AQP1), and type 3 Na+/H+ exchanger (NHE3) from the BBM; 3) redistribution of these transporters into vesicles that were randomly scattered throughout the cell cytoplasm; and 4) redistribution of NHE3, but not megalin, into the basolateral plasma membrane. The internalization of BBM transporters was accompanied by fragmentation and loss of microtubules and by an increased abundance of alpha-tubulin monomers in PT cells. Transporter redistribution was detectable as early as 1 h after Cd-MT treatment and increased in magnitude over the next 12 h. We conclude that the early mechanism of Cd toxicity in PT cells may include a colchicine-like depolymerization of microtubules and impaired vesicle-dependent recycling of various BBM proteins. These processes may lead to a time-dependent loss of cell membrane components, resulting in reabsorptive and secretory defects that occur in Cd-induced nephrotoxicity.
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PMID:Cd-MT causes endocytosis of brush-border transporters in rat renal proximal tubules. 1242 37

The first health effect of cadmium (Cd) was lung damage, reported in workers already in the 1930's, while bone effects and proteinuria 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 cadmium pollution were issued in the 1970's. WHO, 1992, identified renal dysfunction as the critical effect and a crude quantitative evaluation was presented. In the 1990's population groups in China exposed to Cd via rice were studied and new information on skeletal, renal and reproductive toxicity of Cd was obtained in the ChinaCad project. There was a decrease in Bone Mineral Density (BMD), an increased prevalence of fractures and an increased urinary content of marker proteins of renal dysfunction among persons with long term exposure to Cd. The development of such biomarkers can be seen as a result of applied 'proteomics' research. Variation in metallothionein gene expression was related to development of renal dysfunction, supporting the usefulness of this 'genomic' approach. The ongoing rapid development of 'genomics' and 'proteomics' technologies will improve possibilities for molecular epidemiology studies in the future, providing an even better basis for preventive action. In many countries, Cd exposures are now under better control than in the past. The target for the 21st century is to achieve a totally acceptable exposure situation without adverse health effects from Cd.
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PMID:Cadmium and health in the 21st century--historical remarks and trends for the future. 1568 51

Mercury, cadmium, and other heavy metals have a high affinity for sulfhydryl (-SH) groups, inactivating numerous enzymatic reactions, amino acids, and sulfur-containing antioxidants (NAC, ALA, GSH), with subsequent decreased oxidant defense and increased oxidative stress. Both bind to metallothionein and substitute for zinc, copper, and other trace metals reducing the effectiveness of metalloenzymes. Mercury induces mitochondrial dysfunction with reduction in ATP, depletion of glutathione, and increased lipid peroxidation; increased oxidative stress is common. Selenium antagonizes mercury toxicity. The overall vascular effects of mercury include oxidative stress, inflammation, thrombosis, vascular smooth muscle dysfunction, endothelial dysfunction, dyslipidemia, immune dysfunction, and mitochondrial dysfunction. The clinical consequences of mercury toxicity include hypertension, CHD, MI, increased carotid IMT and obstruction, CVA, generalized atherosclerosis, and renal dysfunction with proteinuria. Pathological, biochemical, and functional medicine correlations are significant and logical. Mercury diminishes the protective effect of fish and omega-3 fatty acids. Mercury, cadmium, and other heavy metals inactivate COMT, which increases serum and urinary epinephrine, norepinephrine, and dopamine. This effect will increase blood pressure and may be a clinical clue to heavy metal toxicity. Cadmium concentrates in the kidney, particularly inducing proteinuria and renal dysfunction; it is associated with hypertension, but less so with CHD. Renal cadmium reduces CYP4A11 and PPARs, which may be related to hypertension, sodium retention, glucose intolerance, dyslipidemia, and zinc deficiency. Dietary calcium may mitigate some of the toxicity of cadmium. Heavy metal toxicity, especially mercury and cadmium, should be evaluated in any patient with hypertension, CHD, or other vascular disease. Specific testing for acute and chronic toxicity and total body burden using hair, toenail, urine, serum, etc. with baseline and provoked evaluation should be done.
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PMID:The role of mercury and cadmium heavy metals in vascular disease, hypertension, coronary heart disease, and myocardial infarction. 1740 90

Cadmium (Cd) exposure results in injury to the proximal tubule characterized by polyuria and proteinuria. Kidney injury molecule-1 (Kim-1) is a transmembrane glycoprotein not normally detected in the mature kidney, but is upregulated and shed into the urine following nephrotoxic injury. In this study, we determine if Kim-1 might be a useful early biomarker of Cd nephrotoxicity. Male Sprague-Dawley rats were given daily injections of Cd for up to 12 weeks. Weekly urine samples were analyzed for Kim-1, protein, creatinine, metallothionein, and Clara cell protein CC-16. Significant levels of Kim-1 were detected in the urine by 6 weeks and continued to increase throughout the treatment period. This appearance of Kim-1 occurred 4-5 weeks before the onset of proteinuria, and 1-3 weeks before the appearance of metallothionein and CC-16. Higher doses of Cd gave rise to higher Kim-1 excretion. Reverse transcriptase-polymerase chain reaction (RT-PCR) expression analysis showed that Kim-1 transcript levels were increased after 6 weeks at the low dose of Cd. Immunohistochemical analysis showed that Kim-1 was present in proximal tubule cells of the Cd-treated rats. Our results suggest that Kim-1 may be a useful biomarker of early stages of Cd-induced proximal tubule injury.
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PMID:Kidney injury molecule-1 is an early biomarker of cadmium nephrotoxicity. 1768 58

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.
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PMID:Historical perspectives on cadmium toxicology. 1934 54

As a result of the widespread use of Cd in industry and its extensive dissemination in the environment, there has been considerable interest in the identification of early biomarkers of Cd-induced kidney injury. Kim-1 is a transmembrane glycoprotein that is not detectable in normal kidney, but is up-regulated and shed into the urine following ischemic or nephrotoxic injury. Recent studies utilizing a sub-chronic model of Cd exposure in the rat have shown that Kim-1 is an early urinary marker of Cd-induced kidney injury. Kim-1 was detected in the urine 4-5 weeks before the onset of proteinuria and 1-3 weeks before the appearance of urinary metallothionein and Clara cell protein 16, which are standard markers of Cd nephrotoxicity. In the present study, we have compared the time course for the appearance of Kim-1 in the urine with the time course for the appearance of alpha glutathione-S-transferase (alpha-GST), N-acetyl-beta-D-glucose amidase (NAG) and Cd, each of which have been used or proposed as urinary markers of Cd nephrotoxicity. Adult male Sprague-Dawley rats were given daily subcutaneous injections of 0.6 mg (5.36 micromoles)/kg Cd, 5 days per week for up to 12 weeks. One day each week, 24 h urine samples were collected and analyzed for protein, creatinine and the various markers. The results showed that significant levels of Kim-1 appeared in the urine as early as 6 weeks into the treatment protocol and then continued to rise for the remainder of the 12 week treatment period. By contrast, significant levels of alpha-GST and NAG did not appear in the urine until 8 and 12 weeks, respectively, while proteinuria was not evident until 10 weeks. The urinary excretion of Cd was below the level of detection until week 4 and then showed a slow, linear increase over the next 6 weeks before increasing markedly between weeks 10 and 12. These results provide additional evidence that Kim-1 is a sensitive biomarker of the early stages of Cd-induced proximal tubule injury.
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PMID:Preclinical evaluation of novel urinary biomarkers of cadmium nephrotoxicity. 1937 16

Biomonitoring employs three categories of biomarkers: Biomarkers of exposure, i.e. measurements of metal concentrations in a compartment in the body reflecting external or internal exposure; Biomarkers of effects include early as well as clinical effects. Biomarkers of susceptibility indicate individuals with increased sensitivity of target molecules or metabolism causing increased target dose. The three categories of biomarkers were used in studies of health effects of metal exposures in China. Adverse effects on the kidney tubules with increased levels of the effect biomarkers beta-2-microglobulin in urine (UB2M) and urinary N-acetyl-beta-d-glucosaminidase (UNAG) were found among Cd exposed population groups in China. Among persons exposed to Cd, occupationally or in the general environment, the level of Cd-induced metallothionein mRNA (MTmRNA) in peripheral lymphocytes appeared as a useful indicator of the ability of individuals to synthesize MT. Persons with low MTmRNA levels displayed higher biomarker values of renal tubular damage than persons with high levels of MTmRNA, at comparable levels of urinary Cd. Other studies demonstrated the importance of auto-antibodies against metallothionein in plasma (MTab) in modifying the response to Cd. Persons with high levels of MTab displayed tubular proteinuria at lower levels of urinary Cd than persons with low levels of MTab. Studies in two metal contaminated areas in China demonstrated clear interactions between Cd and inorganic arsenic. Combined exposure, with increased levels of As and Cd in urine, caused considerably higher biomarker values of renal tubular damage, measured as increased urinary levels of B2M or NAG, than each of the exposures alone.
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PMID:Biomarkers of exposure, effects and susceptibility in humans and their application in studies of interactions among metals in China. 1954 Sep 8


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