Cadmium-induced Renal Damage Research Articles

Myo-inositol oxygenase overexpression exacerbates cadmium-induced kidney injury via oxidant stress and necroptosis.

Conceivably, like other forms of acute kidney injury, cadmium-induced renal injury may also be associated with oxidative stress and various forms of cell death, including necroptosis, a form of regulated necrosis-associated cell death. Myo-inositol oxygenase (MIOX), an enzyme localized in renal proximal tubules, regulates oxidative stress and programmed cell death in various forms of renal injuries. Herein, the role and potential mechanism(s) by which MIOX potentiates cadmium-induced renal tubular damage were investigated. Overexpression of MIOX exacerbated cadmium-induced cell death and proximal tubular injury in mice, whereas MIOX gene disruption attenuated cellular damage in vitro and in vivo. Furthermore, necroptosis was observed in the renal tubular compartment, and, more importantly, it was corroborated by inhibitor experiments with necrostatin-1 (Nec-1). Coadministration of Nec-1 dampened including receptor-interacting protein kinase (RIP)1/RIP3/mixed-lineage kinase domain-like signaling, which is relevant to the process of necroptosis. Interestingly, the necroptosis induced by cadmium in tubules was modulated by MIOX expression profile. Also, the increased reactive oxygen species generation and NADPH consumption were accelerated by MIOX overexpression, and they were mitigated by Nec-1 administration. These findings suggest that MIOX-potentiated redox injury and necroptosis are intricately involved in the pathogenesis of cadmium-induced nephropathy, and this may yield novel potential therapeutic targets for amelioration of cadmium-induced kidney injury.NEW & NOTEWORTHY This is a seminal article documenting the role of myo-inositol oxygenase (MIOX), a renal proximal tubule-specific enzyme, in the exacerbation of cadmium-induced acute kidney injury by perturbing redox balance and inducing necroptosis. MIOX gene disruption or administration of necrostatin-1 (a necroptosis inhibitor) diminished cadmium-induced renal damage, in both in vitro and in vivo systems, suggesting a therapeutic potential of MIOX to attenuate necroptosis and relevant signaling pathways in cadmium-induced renal injury.

Targeting oxidative stress, apoptosis, and autophagy by galangin mitigates cadmium-induced renal damage: Role of SIRT1/Nrf2 and AMPK/mTOR pathways

BackgroundGalangin, a bioactive flavonoid with remarkable antioxidant and anti-apoptotic actions, has demonstrated promising amelioration of experimental hepatotoxicity, cardiomyopathy, and colitis. Yet, its impact on cadmium-induced renal injury has not been explored. Herein, we aimed at exploring the potential of galangin to attenuate cadmium-induced nephrotoxicity in rats, focusing on oxidative stress, apoptosis, and autophagy. MethodologyCadmium chloride (5 mg/kg/day) and galangin (15 mg/kg/day) were received by oral gavage and the kidney tissues were inspected using ELISA, biochemical measurements, histology, and immunohistochemistry. Key findingsGalangin attenuated cadmium-induced renal damage by diminishing the histopathological alterations alongside KIM-1, BUN, and creatinine. At the molecular level, galangin attenuated the oxidative insult by significantly lowering the lipid peroxides and NOX-1 and augmenting GSH and GPx antioxidants. It also activated the cytoprotective SIRT1/Nrf2/HO-1 pathway by significantly upregulating the protein expression of SIRT1, Nrf2, and HO-1. Consistently, galangin suppressed renal apoptotic cell death by significantly lowering the protein expression of Bax and cytochrome C and activity of caspase-3 alongside upregulating the protein expression of the anti-apoptotic Bcl-2. Additionally, galangin activated the impaired autophagy flux as seen by diminishing the accumulation of SQSTM1/p62 and increasing the protein expression of Beclin 1. Meanwhile, galangin stimulated the autophagy-linked AMPK/mTOR pathway by significantly increasing the p-AMPK/total AMPK and lowering p-mTOR/total mTOR ratios. ConclusionGalangin mitigated cadmium-induced nephrotoxicity thanks to its promising antioxidant, anti-apoptotic, and pro-autophagic effects. In perspective, galangin stimulated the SIRT1/Nrf2/HO-1 and AMPK/mTOR pathways. Hence, it may act as a complementary tool for the management of cadmium-induced renal injury.

The Association Between Renal Tubular Dysfunction and Zinc Level in a Chinese Population Environmentally Exposed to Cadmium.

Studies in vivo and in vitro have shown a protective effect of zinc against renal dysfunction caused by cadmium exposure. However, limited human data is available. In this study, we evaluated the association between renal tubular dysfunction and body zinc burden in a Chinese population exposed to cadmium. A total of 331 subjects (170 women and 161 men) living in control and cadmium-polluted area were included. Blood cadmium (BCd), urinary cadmium (UCd), serum zinc (SZn), zinc in hair (HZn), Zn/Cd ratio, and urinary β2Microglobulin (UBMG) were measured. The median UCd, BCd, SZn, and HZn were 2.8 and 13.6μg/g cr, 1.3 and 12.2μg/L, 1.31 and 1.12mg/L, and 0.14 and 0.12mg/g in subjects living in control and polluted areas. The UBMG level of subjects living in the polluted area was significantly higher than that of the control (0.27 vs 0.11mg/g cr, p < 0.01). SZn, HZn, and Zn/Cd ratios were negatively correlated with UBMG (p < 0.05 or 0.01). Subjects with high SZn concentrations (≥ 1.62mg/L) had reduced risks of elevated UBMG [(odds ratio (OR) = 0.26, 95% confidence interval (CI) 0.07-0.99)] after controlling for multiple covariates compared with those with lower zinc levels. A similar result was observed in subjects with high HZn (OR = 0.09, 95% CI 0.02-0.48). The ORs of the second, third, and fourth quartiles of Zn/Cd ratio were 0.40 (95% CI 0.19-0.84), 0.14 (95% CI 0.06-0.37), and 0.01 (95% CI 0.02-0.18) for renal dysfunction compared with those of the first quartile, respectively. For those subjects with high level of UCd, high level of SZn and HZn also had reduced risks of elevated UBMG. The results of the present study show that high zinc body burden is associated with a decrease risk of renal tubular dysfunction induced by cadmium. Zinc nutritional status should be considered in evaluating cadmium-induced renal damage.

Selenium and rutin alone or in combination do not have stronger protective effects than their separate effects against cadmium-induced renal damage

Context: Selenium (Se) and rutin (RUT) are antioxidants that protect against tissue damage.Objective: In this study, the separate and combine protective effects of RUT and Se against cadmium (Cd)-induced renal damage were evaluated in rats.Materials and methods: Wistar rats were treated by gavage to RUT (30 mg/kg) or Se (0.15 ppm) or Cd (200 ppm) in drinking water alone or in combination (30 mg/kg RUT +0.15 ppm Se + 200 ppm Cd). Corn oil was used as vehicle (2 mL/kg). After a 5-week treatment period, rat kidneys were removed for biochemical assays and histopathological examination. Se and Cd levels were evaluated by flame atomic absorption spectrophotometry.Results: The malondialdehyde and glutathione levels as well as superoxide dismutase and catalase activities in the Cd-treated animals were increased compared with control values (0.056 ± 0.0003 versus 0.011 ± 0.0005 μmol/mg; 0.005 ± 0.0006 versus 0.00085 ± 0.0002 μg/mg; 1.62 ± 0.09 versus 0.48 ± 0.12 units/mg; 650 ± 25 versus 361.89 ± 31 μmol H2O2/mg, respectively). Cd treatment was also associated with decreased renal Se concentration (4.19 ± 0.92 versus 7.73 ± 0.7 μg/g dry weight), increased alkaline phosphatase (0.07 ± 0.0015 versus 0.033 ± 0.0019 unit/mg), acid phosphatase (0.029 ± 0.0021 versus 0.015 ± 0.0016 unit/mg), and lactate dehydrogenase (0.032 ± 0.004 versus 0.014 ± 0.0027 unit/mg) activities, respectively, and with evidence of severe renal damage. The combination of RUT and Se or their separate effects prevented the Cd-induced oxidative renal damage. However, their combine effects do not have stronger effects than their separate effect against Cd-induced renal damage.Discussion and conclusion: RUT and Se function as potent antioxidant in the protection of renal damage induced by Cd.

Protective effect of caffeic acid phenethyl ester against cadmium-induced renal damage in mice

Cadmium (Cd) is classified as an environmental pollutant and human carcinogen. Caffeic acid phenethyl ester (CAPE), a biological active component of honeybee propolis extracts, has been used as a folk medicine with no harmful effects on normal cells. Here we investigated the beneficial effect of CAPE on Cd-induced renal damage in mice. Since renal damage induced by Cd (II) is related to oxidative stress, lipid peroxidation (LPO), protein carbonyl (PCO), superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) were evaluated. Moreover, the concentrations of Cd and zinc (Zn) in the kidney were analyzed. The intoxication of Cd (II) leads to the enhanced production of LPO and PCO, and the decrease of SOD activity and GSH level, probably due to the serious oxidative stress. However, the activities of CAT in the Cd (II)-induced group showed an elevated tendency, probably relating to an adaptive-response to the oxidative damage. The co-administration of CAPE can attenuate the oxidative stress caused by the intoxication of Cd and restore the altered antioxidant defense system. Based on our data, it is proposed that CAPE may involve in the protection of renal damage induced by Cd (II) owing to its antioxidant capacity and anti-inflammatory effect.

Taurine plays a beneficial role against cadmium-induced oxidative renal dysfunction.

The present study has been carried out to investigate the role of taurine (2-aminoethanesulfonic acid), a conditionally essential amino acid, in ameliorating cadmium-induced renal dysfunctions in mice. Cadmium chloride (CdCl(2)) has been selected as the source of cadmium. Intraperitoneal administration of CdCl(2 )(at a dose of 4 mg/kg body weight for 3 days) caused significant accumulation of cadmium in renal tissues and lessened kidney weight to body weight ratio. Cadmium administration reduced intracellular ferric reducing/antioxidant power (FRAP) of renal tissues. Levels of serum marker enzymes related to renal damage, creatinine and urea nitrogen (UN) have been elevated due to cadmium toxicity. Cadmium exposure diminished the activities of enzymatic antioxidants, superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), glutathione reductase (GR), glutathione peroxidase (GPx) and glucose-6-phosphate dehydrogenase (G6PD) as well as non-enzymatic antioxidant, reduced glutathione (GSH) and total thiols. On the other hand, the levels of oxidized glutathione (GSSG), lipid peroxidation, protein carbonylation, DNA fragmentation, concentration of superoxide radicals and activities of cytochrome P450 enzymes (CYP P450s) have been found to increase due to cadmium intoxication. Treatment with taurine (at a dose of 100 mg/kg body weight for 5 days) before cadmium intoxication prevented the toxin-induced oxidative impairments in renal tissues. The beneficial role of taurine against cadmium-induced renal damage was supported from histological examination of renal segments. Vitamin C, a well-established antioxidant was used as the positive control in the study. Experimental evidence suggests that both taurine and vitamin C provide antioxidant defense against cadmium-induced renal oxidative injury. Combining all, results suggest that taurine protects murine kidneys against cadmium-induced oxidative impairments, probably via its antioxidative property.

Cadmium toxicity to ringed seals ( Phocahispida): an epidemiological study of possible cadmium-induced nephropathy and osteodystrophy in ringed seals ( Phoca hispida) from Qaanaaq in Northwest Greenland

The Greenland marine food chains contain high levels of cadmium, mercury and selenium. Concentrations of cadmium in the kidney of ringed seals ( Phoca hispida) from the municipalities of Qaanaaq and Upernavik (Northwest Greenland) are among the highest recorded in the Arctic. The purpose of the study was to determine whether cadmium-induced damage in the kidneys and the skeletal system could be detected among 100 ringed seals from Northwest Greenland. The cadmium concentrations in the kidney cortex ranged from 0 to 248 μg/g wet weight (mean=44.5, N=100) in the 99 kidneys examined. Experience from cadmium-poisoned humans and laboratory mammals indicates that concentrations above 50–200 μg/g wet wt. may induce histopathological changes. Overall, 31 of the ringed seals had cadmium concentrations in the kidney cortex above 50 μg/g wet wt., 11 had concentrations above 100 and one had a concentration above 200 μg/g wet wt. Obvious histopathological changes (categorised mainly as glomerulonephritis) were found in 10 of the seals; however, none of these changes could be attributed to cadmium-induced renal damage (mainly tubulopathy) as described for other species. Damage to the proximal kidney tubules is known to induce demineralisation of the skeletal system (Fanconi's syndrome). Therefore, the three lowest lumbar vertebrae were scanned in 91 seals to measure the content of calcium. The 10 cases of nephropathy could neither be linked to the degree of mineralisation of the skeleton nor to the cadmium concentrations. Furthermore, the degree of mineralisation of the skeleton was not correlated with the cadmium concentration, age or sex. It can therefore be concluded that despite high levels of cadmium, none of the ringed seals showed any signs of cadmium-induced nephropathy or osteodystrophy. This might be explained by the composition of the ringed seals diet, which contains high levels of vitamin D, calcium, phosphorus, zinc, selenium and protein. These elements are all likely to counteract cadmium-induced damage. It is speculated that ringed seal are not particularly vulnerable to osteodystrophy, due to their continuous growth (bone mineralisation) throughout life and the oestrogen hormonal activity of females throughout life.

Cadmium-Induced Renal Damage and Proinflammatory Cytokines: Possible Role of IL-6 in Tubular Epithelial Cell Regeneration

Cadmium exposure in humans and experimental animals produces renal damage characterized by degeneration and necrosis of tubular epithelial cells followed by interstitial inflammation and eventual regeneration of proximal tubular cells. Since chronic kidney diseases are often associated with the presence of inflammatory cytokines and cadmium has been reported to alter cytokine expression in monocytes and the Kupffer cells of the liver, we investigated the role of proinflammatory cytokines in cadmium-induced nephrotoxicity. Increases in TNF-α and IL-6 cytokine mRNA transcripts and secretion were observed in the kidney following exposure of LPS-primed mice to a total of 21 mg/kg body weight cadmium administered over a 14-week period. IL-6 was the predominant cytokine expressed and was found to be present in mesangial cells. Cadmium, in the presence of LPS, was able to induce IL-6 secretion in vitro from mouse glomerular mesangial cells. Proliferative cell nuclear antigen (PCNA) staining revealed increases in regeneration of tubular epithelial cells following cadmium exposure. Furthermore, renal tubular epithelial cells responded to IL-6 by marked proliferation. Taken together, these data suggest that cadmium-induced IL-6 secretion in the kidney may act to support the regeneration of renal tubular epithelial cells that occurs in the course of cadmium nephrotoxicity.

Adverse health effects in workers exposed to cadmium.

One hundred fifty-two workers who had been exposed to different levels of cadmium (Cd) absorption (blood Cd mean 16.34 micrograms/L, median 11.0 micrograms/L) in a factory making nickel-cadmium batteries were studied. A physical evaluation, as well as blood and urine cadmium and N-acetyl-beta-D-glucosaminidase (NAG), and other routine laboratory tests were performed in order to assess the relationship between different levels of exposure to occupational cadmium and potential cadmium-induced renal damage and other adverse health effects. We found significant correlation between levels of cadmium exposure and a selected group of symptoms and signs. The best predictor of this group of symptoms and signs was an indicator called internal dose index (Cd x exposure time). This indicator appears as the strongest, even after control by confounding factors, such as age and smoking. It is concluded that this index can be used for biological monitoring.

Effect of N-benzyl- d-glucamine dithiocarbamate on the renal toxicity produced by subacute exposure to cadmium in rats

The effect of N-benzyl- d-glucamine dithiocarbamate (BGD) on the renal toxicity produced by subacute exposure to cadmium in rats was studied. Rats were injected sc with CdCl 2 (1.5 mg Cd/kg) daily for 26 days and thereafter they received 13 injections of BGD (400 μmol/kg) every other day. Urinary protein concentration and AST activity significantly increased after 20 days of cadmium treatment. The pattern of the increase in the urinary excretion of cadmium after cadmium treatment was consistent with that in the urinary excretion of protein and AST. Urinary excretion of amino acid increased gradually after the cessation of cadmium treatment. BGD treatment significantly decreased the urinary excretion of protein, aspartate aminotransferase (AST), and amino acid. Plasma AST activity was elevated 8 days after the beginning of cadmium treatment, indicating that the hepatic damage occurred prior to the renal damage. In addition, the microscopic examination of renal tissue from cadmium-treated rats revealed the necrosis of the proximal tubular cells. The cadmium concentrations in liver and kidney were significantly decreased by BGD treatment. The results of this study indicate that BGD treatment is effective in decreasing the cadmium concentrations in liver and kidney, resulting in the therapeutic effect on the cadmium-induced renal damage.

Kidney changes in multiparous mice fed a nutrient-sufficient diet containing cadmium

Female mice were given nutrient-sufficient, purified diets containing cadmium at either 0.25, 5, or 50 ppm, as described in the accompanying publication [1]. One-half of the females were bred for 6 consecutive 42-day rounds of pregnancy/lactation (PL mice); remaining females were non-pregnant controls (NP mice). PL mice and NP controls were sacrified after 1, 2, 4, or 6 consecutive rounds of pregnancy/lactation. At all levels of dietary cadmium and after all reproductive rounds, kidney cadmium concentrations were 2–5-fold higher in PL than NP mice. After 6 rounds of reproduction, the mean concentration of cadmium in the kidneys of PL mice exposed to dietary cadmium at 50 ppm was 115 μg Cd/g kidney, close to the critical concentration for cadmium-induced renal damage (200 μg/g). No consistent increases in the concentrations of amino acids, protein, or cadmium in urine were observed in the NP or PL mice in our study, indicating that cadmium-induced renal dysfunction had not yet appeared. Very small increases in kidney concentrations of zinc and copper were observed with large increases in kidney cadmium concentrations. Threshold cadmium concentrations below which the concentrations of zinc and copper were relatively constant and independent of cadmium concentration were identified; they were 7.2 μg Cd/g kidney for zinc and 13 μg Cd/g kidney for copper. In this study, cadmium-induced decreases in bone-mineral content occurred in the PL mice exposed to cadmium at 5 and 50 ppm (see accompanying publication). Data presented here indicate that the latter bone changes occurred in the absence of cadmium-induced renal dysfunction of the type that results in increased aminoaciduria/proteinuria. They suggest that the bone disease of Itai-Ital patients may also have started prior to the onset of this type of renal dysfunction.

Parathyroid hormone concentration in the serum of people with cadmium-induced renal damage.

Serum parathyroid hormone (PTH) and renal functions were measured in thirty subjects with cadmium-induced renal damage and in the same number of control subjects. The negative correlations between PTH and creatinine clearance (Ccr) and between PTH and percentage renal phosphorus reabsorption (% TRP) were significant in the cadmium (Cd)-exposed group. Serum PTH concentrations were clearly high in two cases of the cadmium-exposed group. Their renal functions decreased severely compared with those of the other Cd-exposed people. The present study indicates that chronic cadmium intoxication could cause increased secretions of PTH, which may be related to cadmium-induced bone damage.

Renal handling of human beta 2-microglobulin in normal and cadmium-poisoned rats.

The renal handling of human beta 2-microglobulin (beta 2-m) was investigated in normal rat and in rat with cadmium-induced renal damage. Cadmium was administered either in drinking water at a concentration of 100 ppm for up to 16 months or by i.p. injection of 1 mg Cd/kg, five times a week for up to 4 months. When renal dysfunction has developed, namely after 2 and 10 months of the i.p. and oral treatment respectively, unlabelled human beta 2-m was injected intravenously and its disappearance in serum and its urinary excretion were studied by means of a sensitive immunoassay. In serum, the level of beta 2-m drops by about 90% during the 10 first min, then declines more slowly with a half life around 20 min. Serum disappearance curves of beta 2-m in normal and cadmium-treated rats did not differ markedly. The amount of beta 2-m recovered in urine during the 4 h following the injection averaged 0.03% of the injected dose in normal rats. It increased on the average to 10% in rats treated i.p. with 1 mg Cd/kg for 3 months. However, in rats given 100 ppm Cd per os for 10 months, this amount averaged only 0.14%. A similar value was observed 5 months later, although at that stage, the critical level of cadmium in kidney cortex had been reached for 6-7 months. These data which were in accordance with the disturbances of the other renal parameters measured in cadmium-treated rats indicate that: 1) human beta 2-m is reabsorbed by rat kidney at a similar rate as by human kidney; 2) if the occurrence of cadmium tubulopathy is concomitant with the saturation of cadmium-binding sites in kidney, its severity depends greatly on the rate at which cadmium reaches the saturated kidneys.

The relationship of dietary protein to metallothionein and cadmium-induced renal damage

The effect of dietary protein on the concentration of kidney metallothionein and cadmium in relationship to renal damage was investigated. Rats fed a low-protein diet accumulated significantly less cadmium in the kidney, liver, lung, and small intestine than rats fed a normal or high-protein diet. Metallothionein synthesis and/or storage was significantly reduced in rats fed the low-protein diet compared with rats fed the normal or high-protein diet. In rats fed the high-protein diet extensive proximal renal tubular necrosis was observed when kidney cadmium was below 200 μg/g wet weight and metallothionein was above 740 μg/g wet weight. Proximal tubular necrosis was slight to moderate in rats fed the normal or low-protein diet, which correlated with relatively low levels of cadmium and metallothionein in the kidney. These studies show that dietary protein affects the tissue level of both cadmium and metallothionein. The results also demonstrate that extensive renal damage can occur when the level of kidney cadmium is below the suggested critical concentration of 200 μg/g wet weight. Based on studies which show the nephrotoxic effects of cadmium-metallothionein and results of the present experiments, we suggest that the concentration of this complex in the kidney is of greater pathological importance than the level of kidney cadmium.