Stress proteins in experimental nephrotoxicity: a ten year experience (original) (raw)
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Mercury Induces Regional and Cell-Specific Stress Protein Expression in Rat Kidney
Toxicological Sciences, 2000
Cells respond to physiologic stress by enhancing the expression of specific stress proteins. Heat-shock proteins (hsps) and glucoseregulated proteins (grps) are members of a large superfamily of proteins collectively referred to as stress proteins. This particular stress-protein response has evolved as a cellular strategy to protect, repair, and chaperone other essential cellular proteins. The objective of this study was to evaluate the differential expression of four hsps in the renal cortex and medulla during experimental nephrotoxic injury using HgCl 2 . Male Sprague-Dawley rats received single injections of HgCl 2 (0.25, 0.5, or 1 mg Hg/kg, iv). At 4, 8, 16, or 24 h after exposure, kidneys were removed and processed for histopathologic, immunoblot, and immunohistochemical analyses. Nephrosis was characterized as minimal or mild (cytoplasmic condensation, tubular epithelial degeneration, single cell necrosis) at the lower exposures, and progressed to moderate or severe (nuclear pyknosis, necrotic foci, sloughing of the epithelial casts into tubular lumens) at the highest exposures. Western blots of renal proteins were probed with monoclonal antibodies specific for 4 hsps. In whole kidney, Hg(II) induced a time-and dose-related accumulation of hsp72 and grp94. Accumulation of hsp72 was predominantly localized in the cortex and not medulla, while grp94 accumulated primarily in the medulla but not cortex. The high, constitutive expression of hsp73 did not change as a result of Hg(II) exposure, and it was equally localized in cortex and medulla. Hsp90 was not detected in kidneys of control or Hg-treated rats. Since hsp72 has been shown involved in cellular repair and recovery, and since Hg(II) damage occurs primarily in cortex, we investigated the cell-specific expression of this hsp. Hsp72 accumulated primarily in undamaged distal convoluted tubule epithelia, with less accumulation in undamaged proximal convoluted-tubule epithelia. These results demonstrate that expression of specific stress proteins in rat kidney exhibits regional heterogeneity in response to Hg(II) exposure, and a positive correlation exists between accumulation of some stress proteins and acute renal cell injury. While the role of accumulation of hsps and other stress proteins in vivo prior to or concurrent with nephrotoxicity remains to be completely understood, these stress proteins may be part of a cellular defense response to nephrotoxicants. Conversely, renal tubular epithelial cells that do not or are unable to express stress proteins, such as hsp72, may be more susceptible to nephrotoxicity.
Toxicology, 2009
A close link between stress protein up-regulation and oxidative damage may provide a novel therapeutic tool to counteract nephrotoxicity induced by toxic metals in the human population, mainly in children, of industrialized countries. Here we analysed the time course of the expression of several heat shock proteins, glucose-regulated proteins and metallothioneins in a rat proximal tubular cell line (NRK-52E) exposed to subcytotoxic doses of inorganic mercury and lead. Concomitantly, we used morphological and biochemical methods to evaluate metal-induced cytotoxicity and oxidative damage. In particular, as biochemical indicators of oxidative stress we detected reactive oxygen species (ROS) and nitrogen species (RNS), total glutathione (GSH) and glutathione-S-transferase (GST) activity. Our results clearly demonstrated that mercury increases ROS and RNS levels and the expressions of Hsp25 and inducible Hsp72. These findings are corroborated by evident mitochondrial damage, apoptosis or necrosis. By contrast, lead is unable to up-regulate Hsp72 but enhances Grp78 and activates nuclear Hsp25 translocation. Furthermore, lead causes endoplasmic reticulum (ER) stress, vacuolation and nucleolar segregation. Lastly, both metals stimulate the over-expression of MTs, but with a different time course. In conclusion, in NRK-52E cell line the stress response is an early and metal-induced event that correlates well with the direct oxidative damage induced by mercury. Indeed, different chaperones are involved in the specific nephrotoxic mechanism of these environmental pollutants and work together for cell survival.
The role of endoplasmic reticulum stress in renal damage caused by acute mercury chloride poisoning
The Journal of Toxicological Sciences
Acute mercury chloride (HgCl 2) poisoning may lead to kidney injury, but the underlying mechanism remains largely unknown. Endoplasmic reticulum (ER) stress plays a role in some heavy metal poisoning. Whether it mediates kidney injury in acute HgCl 2 poisoning remains unknown. In this study, we examined the kidney injury and the corresponding ER stress in the mouse model of different doses of acute HgCl 2 poisoning. To further confirm the role of ER stress, we tested the effects of its chemical chaperone [4-phenylbutyric acid (4-PBA)]. The results revealed that acute HgCl 2 poisoning caused more severe kidney injury with dose on and activated ER stress, as indicated by increased expression of GRP78 and CHOP. Inhibition of ER stress restored the functional and morphological changes of kidneys, and partly attenuated renal tubular epithelial cell apoptosis. In summary, ER stress contributes to the acute kidney injury following HgCl 2 poisoning, and inhibition of ER stress may alleviate the kidney injury via reducing apoptosis.
Mercuric chloride-induced alterations in stress protein distribution in rat kidney
Histology and histopathology, 2004
Mercuric chloride (HgCl2) induces acute renal failure associated to tubular impairment in experimental animals and humans. Stress proteins are a superfamily of proteins, comprising heat- shock proteins (HSP) and glucose-regulated proteins (GRP), enhanced or induced in the kidney in response to stress. They act as molecular chaperones that protect organelles and repair essential proteins which have been denatured during adverse conditions. The involvement of stress proteins in mercury-nephrotoxicity has not yet been well clarified. This study was undertaken to detect the tubular distribution of four stress proteins (HSP25, HSP60, GRP75, HSP72) in the rat kidney injected with HgCl2 and to quantify lysosomal and mitochondrial changes in straight proximal tubules, the main mercury target. Sprague-Dawley rats were administered i.p. with progressive sublethal doses of HgCl2 (0.25 mg/kg, 0.5 mg/kg, 1 mg/kg and 3.5 mg/kg) or saline (as controls) and sacrificed after 24 h. In dosages over 0....
Stress proteins expression in rat kidney and liver chronically exposed to aluminium sulphate
Histology and histopathology, 2006
Aluminium (Al) is the third most widespread metal in the environment. It is toxic for the brain, bone and haematological system but unfortunately very little data exist for other organs. Stress proteins are induced or enhanced against metal toxicity with an essential role in the recovery of organules and other cellular proteins. This immunohistochemical study was performed to analyze the distribution of three stress proteins (HSP25, HSP72, GRP75) in rat kidney and liver orally exposed to Al sulphate daily for 3 and 6 months. Al-induced alterations were further studied by histopathology (H-E, PAS, Perl's, Masson) and ultrastructural morphometry. In the kidney: HSP25 was enhanced in proximal tubules after 6 months Al-exposure when abnormal brush borders were observed; HSP72 was induced in proximal tubules only after long Al-treatment; GRP75 was raised in midcortical area sometimes within nuclei. Furthermore, lysosomal and lipofuscins densities increased in the juxtamedullary tubul...
Proceedings of the National Academy of Sciences, India Section B: Biological Sciences, 2024
Chronic exposure to heavy metals, such as arsenic, cadmium and lead, causes serious health issues and reproductive impairment. Therefore, the heavy metal exposure and its resultant stress may change the expression of some genes. Thus, this work aims to find the differential expression pattern of stress proteins such as heat shock protein 70 (HSP70) and metallothioneins (MT1 and MT2) in testes and liver tissue of juvenile and adult rats after chronic treatment of these heavy metals. In general, testicular tissue was selected to review the reproductive health, and liver was selected as the tissue for drug and metal detoxification. Triplicate sets of male Wistar rats both juvenile (15 days old) and adult (2 months old) were taken as treated study subjects. They were supplied drinking water having heavy metal salts of dose 100 times higher than maximum contamination limit, as sole water source, for 3 months. Similarly, triplicate sets of age-matched controls were supplied heavy metal-free distilled water for same duration. After treatment period, semi-quantitative RT-PCR was done to study the expression level of above-mentioned stress proteins in testes and liver in all subjects. Results showed that there was a consistent and significant increase in expression of MT1 compared to controls (p < 0.05), especially in liver tissue after chronic exposure to heavy metals. Overall, this work corroborates that chronic exposure of heavy metal at early age can cause a serious health impact on later stage of life.
Induction of stress proteins in human endothelial cells by heavy metal ions and heat shock
American Journal of Physiology-Lung Cellular and Molecular Physiology
In the present study, we compared the induction of heat shock proteins (HSPs) by heat and heavy metal ions in three different endothelial cell types, namely, human umbilical vein endothelial cells, human pulmonary microvascular endothelial cells, and the cell line EA.hy 926. Our results show that especially Zn2+ and Cd2+ are inducers of 70-kDa (HSP70), 60-kDa (HSP60), 32-kDa (HSP32), and 27-kDa (HSP27) HSPs. The strength of inducibility is specific for each HSP. Ni2+ and Co2+ only show an inducible effect at very high concentrations, that is, in the clearly cytotoxic range. Furthermore, we investigated the time course of HSP expression and the involvement of heat shock factor-1. Our study demonstrates that the three endothelial cell types that were under investigation show comparable stress protein expression when treated with heavy metal ions or heat shock. The expression of stress proteins may be used as an early marker for the toxic damage of cells. This damage can be an inducer ...
Bimoclomol ameliorates mercuric chloride nephrotoxicity through recruitment of stress proteins
Toxicology Letters, 2006
Bimoclomol (BIM), is a stress proteins coinducer, that acts synergistically with a mild stressor to activate cytoprotective stress proteins. BIM has been successfully utilized in animal models for the treatment of various nervous, cardiac and cerebrovascular diseases. Mercuric chloride (HgCl 2 ) induces acute renal failure in rats by a single dosage. The present in vivo study was conducted to assess the efficacy of BIM against acute HgCl 2 nephrotoxicity. At different times after BIM and/or HgCl 2 exposure we evaluated renal morphology and the localization/abundance of three stress proteins (HSP72, GRP75, HSP60) by electron microscopy, immunohistochemistry and Western blot analysis. BIM delivery to rats 6 h before mercury, ameliorated damage to renal ultrastructure, with recovery of tubular and mitochondrial membranes 24 h after mercury treatment. In rats pretreated with BIM prior to HgCl 2 exposure, HSP72 was significantly overexpressed in proximal tubules in a time-dependent manner. In contrast, the amounts of GRP75 and HSP60 after BIM pretreatment were comparable to the group treated with mercury alone, but these stress proteins had translocated to the nuclei at 14 and 24 h, respectively.
Tight junction proteins and oxidative stress in heavy metals-induced nephrotoxicity
BioMed research international, 2013
Kidney is a target organ for heavy metals. They accumulate in several segments of the nephron and cause profound alterations in morphology and function. Acute intoxication frequently causes acute renal failure. The effects of chronic exposure have not been fully disclosed. In recent years increasing awareness of the consequences of their presence in the kidney has evolved. In this review we focus on the alterations induced by heavy metals on the intercellular junctions of the kidney. We describe that in addition to the proximal tubule, which has been recognized as the main site of accumulation and injury, other segments of the nephron, such as glomeruli, vessels, and distal nephron, show also deleterious effects. We also emphasize the participation of oxidative stress as a relevant component of the renal damage induced by heavy metals and the beneficial effect that some antioxidant drugs, such as vitamin A (all-trans-retinoic acid) and vitamin E ( α -tocopherol), depict on the morph...