Proximal tubular transport of Metallothionein-Mercury complexes and protection against nephrotoxicity.

Mercury (Hg) is an important environmental toxicant to which humans are exposed on a regular basis. Mercuric ions within biological systems do not exist as free ions. Rather, they are bound to free sulfhydryl groups (thiols) on biological molecules. Metallothionein (MT) is a cysteine-rich, metal-binding protein that has been shown to bind to heavy metals and reduce their toxic effects in target cells and organs. Little is known about the effect of MT on the handing and disposition of Hg. Therefore, the current study was designed to test the hypothesis that overexpression of MT alters the corporal disposition of Hg and reduces its nephrotoxicity. Furthermore, the current study examined the transport of Hg-MT complexes in isolated proximal tubules. Rats were treated with saline or Zn followed by injection with a non-nephrotoxic (0.5 µmol kg-1), moderately nephrotoxic (1.5 µmol kg-1), or significantly nephrotoxic (2.25 µmol kg-1) dose of HgCl2 (containing radioactive Hg). Pretreatment with Zn increased mRNA expression of MT and enhanced accumulation of Hg in the renal cortex of male and female rats. In addition, injection with Zn also protected animals from Hg-induced nephrotoxicity. Studies using isolated proximal tubules from rabbit kidney demonstrated that Hg-MT is taken up rapidly at the apical and basolateral membranes. The current findings suggest that at least part of this uptake occurs through an endocytic process. This study is the first to examine the uptake of Hg-MT complexes in isolated proximal tubules. Overall, the findings of this study suggest that supplementation with Zn may be a viable strategy for reducing the risk of Hg intoxication in at-risk populations.

Hepatic processing of mercuric ions facilitates delivery to renal proximal tubules.

Mercury (Hg) is a toxic heavy metal to which humans are exposed on a regular basis. Hg has a high affinity for thiol-containing biomolecules with the majority of Hg in blood being bound to albumin. The current study tested the hypothesis that circulating Hg-albumin complexes are taken up into hepatocytes and processed to form Hg-glutathione (GSH) conjugates (GSH-Hg-GSH). Subsequently, GSH-Hg-GSH conjugates are exported from hepatocytes into blood via multidrug resistance transporters (MRP) 3 and 5. To test this hypothesis, the portal vein and hepatic artery in Wistar rats were ligated to prevent delivery of Hg to the liver. Ligated and control rats were injected with HgCl2 or GSH-Hg-GSH (containing radioactive Hg) and the disposition of Hg was assessed in various organs. Renal accumulation of Hg was reduced significantly in ligated rats exposed to HgCl2. In contrast, when rats were exposed to GSH-Hg-GSH, the renal accumulation of Hg was similar in control and ligated rats. Experiments using HepG2 cells indicate that Hg-albumin conjugates are taken up by hepatocytes and additional experiments using inside-out membrane vesicles showed that MRP3 and MRP5 mediate the export of GSH-Hg-GSH from hepatocytes. These data are the first to show that Hg-albumin complexes are processed within hepatocytes to form GSH-Hg-GSH, which is, in part, exported back into blood via MRP3 and MRP5 for eventual excretion in urine.

Prophylactic supplementation with selenium alters disposition of mercury in aged rats.

Mercury (Hg) is a prevalent environmental toxicant to which older individuals are particularly susceptible. Selenium (Se) has been used as an antidote following exposure to Hg. However, little is known about the effect of prophylactic supplementation with Se on the handling of Hg. The current study was designed to test the hypothesis that oral pre-treatment with Se alters the corporal disposition of Hg and reduces the risk of Hg-induced toxicity. Young and aged rats were gavaged for 10 days with sodium selenite or saline. On day 11, rats were injected intravenously with 0.5 µmol HgCl2·kg-1·2 mL-1 normal saline. After 24 h, rats were euthanized and organs and tissues were harvested for determination of Hg content. Accumulation of Hg in the kidney was reduced significantly by pre-treatment with Se in both young and aged rats. In the renal cortex, the magnitude of the reduction was greater in aged rats than in young rats but in the outer stripe of the outer medulla, the magnitude of the reduction was similar between groups of rats. Urinary excretion of Hg was also reduced in rats pre-treated with Se. In contrast, the hepatic and hematologic burden of Hg increased in rats pre-treated with Se. Fecal excretion of Hg was decreased significantly by pre-treatment with Se in young rats but not in aged rats. These data suggest that prophylactic supplementation with Se alters the corporal disposition of Hg in a way that may reduce Hg-induced toxicity in target organs.

Transport and Toxicity of Methylmercury-Cysteine in Cultured BeWo Cells.

Mercury is a heavy metal toxicant that is prevalent throughout the environment. Organic forms of mercury, such as methylmercury (MeHg), can cross the placenta and can lead to lasting detrimental effects in the fetus. The toxicological effects of MeHg on the placenta itself have not been clearly defined. Therefore, the purpose of the current study was to assess the transport of MeHg into placental syncytiotrophoblasts and to characterize the mechanisms by which MeHg exerts its toxic effects. Cultured placental syncytiotrophoblasts (BeWo) were used for these studies. The transport of radioactive MeHg was measured to identify potential mechanisms involved in the uptake of this compound. The toxicological effects of MeHg on BeWo cells were determined by assessing visible pathological change, autophagy, mitochondrial viability, and oxidative stress. The findings of this study suggest that MeHg compounds are transported into BeWo cells primarily by sodium-independent amino acid carriers and organic anion transporters. The MeHg altered mitochondrial function and viability, decreased mitophagy and autophagy, and increased oxidative stress. Exposure to higher concentrations of MeHg inhibited the ability of cells to protect against MeHg-induced injury. The findings show that MeHg is directly toxic to syncytiotrophoblasts and may lead to disruptions in the fetal/maternal transfer of nutrients and wastes.

Reaction of Cyanide with Hg0-Contaminated Gold Mining Tailings Produces Soluble Mercuric Cyanide Complexes.

Elemental mercury (Hg0) contamination in artisanal and small-scale gold mining (ASGM) communities is widespread, and Hg0-contaminated tailings are often reprocessed with cyanide (-CN) to extract residual gold remaining after amalgamation. Hg0 reacts with -CN under aerobic conditions to produce Hg(CN)42- and other Hg(CN)nn-2 complexes. The production of solvated Hg(CN)nn-2 complexes increases upon agitation in the presence of synthetic and authentic Hg0-contaminated tailings that aid in dispersing the Hg0, increasing its reactive surface area. Adult rats were exposed to various concentrations of Hg(CN)2, and accumulation in organs and tissues was quantified using direct mercury analysis. The primary site of Hg(CN)2 accumulation was the kidney, although accumulation was also detected in the liver, spleen, and blood. Little accumulation was observed in the brain, suggesting that Hg(CN)2 complexes do not cross the blood-brain barrier. Renal tissue was particularly sensitive to the effects of Hg(CN)2, with pathological changes observed at low concentrations. Hg(CN)2 complexes are handled by mammalian systems in a manner similar to other inorganic species of Hg, yet appear to be more toxic to organ systems. The findings from this study are the first to show that Hg(CN)2 complexes are highly stable complexes that can lead to cellular injury and death in mammalian organ systems.

Chronic kidney disease in pregnant mothers affects maternal and fetal disposition of mercury.

Chronic kidney disease (CKD) affects over 15 % of the adults in the United States. Pregnant women with CKD present an additional challenge in that they are at increased risk for adverse events such as preterm birth. Exposure to environmental toxicants, such as methylmercury, may exacerbate maternal disease and increase the risk of adverse fetal outcomes. We hypothesized that fetuses of mothers with CKD are more susceptible to accumulation of methylmercury than fetuses of healthy mothers. The current data show that when mothers are in a state of renal insufficiency, uptake of mercury in fetal kidneys is enhanced significantly. Accumulation of Hg in fetal kidneys may be related to the flow of amniotic fluid, maternal handling of Hg, and/or underdeveloped mechanisms for cellular export and urinary excretion. The results of this study indicate that renal insufficiency in mothers leads to significant alterations in the way toxicants such as mercury are handled by maternal and fetal organs.

Sex differences in renal handling of inorganic mercury in aged rats.

The sex of an individual/animal has been shown to play an important role in many biological processes. Furthermore, sex may also be a factor in the way environmental toxicants, such as heavy metals, are handled by organisms. However, the effect of sex on the handling and disposition of heavy metals, such as mercury (Hg), has not been shown. Aging has also been shown to be a factor in the accumulation of heavy metals in that older individuals tend to have higher burdens of these metals. Therefore, the purpose of the current study was to evaluate the effect of sex on the accumulation of mercury in aged animals. Aged male and female rats were injected intravenously with 0.5 µmol or 2.0 µmol·kg-1 HgCl2 (containing radioactive Hg) and organs were harvested after 24 h. In general, the renal accumulation of Hg was significantly greater in males than in females. Similarly, urinary excretion of Hg was greater in males than in females. There were no significant differences between males and females in the burden of Hg in other organs. Sex differences in the renal accumulation of Hg may be related to differences in the expression of membrane transporters involved in the uptake of mercuric species into tubular epithelial cells. The results of the current study illustrate the need to evaluate both sexes when assessing the renal effects of environmental toxicants.

Co-administration of Selenium with Inorganic Mercury Alters the Disposition of Mercuric Ions in Rats.

Mercury (Hg) is a common environmental toxicant to which humans are exposed regularly through occupational and dietary means. Although selenium supplementation has been reported to prevent the toxic effects of Hg in animals, the mechanisms for this prevention are not well understood. The purpose of the current study was to determine the effects of selenium on the disposition and toxicity of Hg. Wistar rats were injected intravenously with a non-nephrotoxic dose (0.5 µmol kg-1) or a nephrotoxic dose (2.5 µmol kg-1) of HgCl2 (containing radioactive Hg) with or without co-administration of sodium selenite (Na2SeO3). Twenty-four hours after exposure, rats were euthanized, and organs were harvested. Co-administration of SeO32- with HgCl2 reduced the renal burden of Hg and the urinary excretion of Hg while increasing the amount of Hg in blood and spleen. We propose that Hg reacts with reduced selenite in the blood to form large Hg-Se complexes that are unable to be filtered at the glomerulus. Consequently, these complexes remain in the blood and are able to accumulate in blood-rich organs. These complexes, which may have fewer toxic effects than other species of Hg, may be eliminated slowly over the course of weeks to months.

Potential mechanisms of cellular injury following exposure to a physiologically relevant species of inorganic mercury.

Mercury is a toxic metal that is found ubiquitously in the environment. Humans are exposed to different forms of mercury via ingestion, inhalation, and/or dermal absorption. Following exposure, mercuric ions may gain access to target cells and subsequently lead to cellular intoxication. The mechanisms by which mercury accumulation leads to cellular injury and death are not understood fully. Therefore, purpose of this study was to identify the specific intracellular mechanisms that are altered by exposure to inorganic mercury (Hg2+). Normal rat kidney (NRK) cells were exposed to a physiologically relevant form of Hg2+, as a conjugate of cysteine (10 µM or 50 µM). Alterations in oxidative stress were estimated by measuring lipid peroxidation and mitochondrial oxidative stress. Alterations in actin and tubulin were measured using specific fluorescent dyes. Calcium levels were measured using Fluo-3 AM Calcium Indicator while autophagy was identified with Premo™ Autophagy Sensor LC3B-GFP. The current findings show that exposure to Hg2+ leads to enhanced oxidative stress, alterations in cytoskeletal structure, increases in intracellular calcium, and enhanced autophagy. We have established a more complete understanding of intoxication and cellular injury induced by a relevant form of Hg2+ in proximal tubule cells.

Exposure to mixtures of mercury, cadmium, lead, and arsenic alters the disposition of single metals in tissues of Wistar rats.

Humans throughout the world are exposed regularly to mixtures of environmental toxicants. Four of the most common heavy metal toxicants in the environment are mercury (Hg), cadmium (Cd), lead (Pb), and arsenic (As). Numerous studies have assessed the effects and disposition of individual metals in organ systems; however, humans are usually exposed to mixtures of toxicants or metals rather than to a single toxicant. Therefore, the purpose of the current study was to test the hypothesis that exposure to a mixture of toxic heavy metals alters the disposition of single metals in target organs. Wistar rats (Rattus norvegicus) were exposed to Hg, Cd, Pb, or As as a single metal or as a mixture of metals. Rats were injected intravenously for three days, following which kidneys, liver, brain, and blood were harvested. Samples were analyzed for content of Hg, Cd, Pb, and As via inductively coupled plasma mass spectrometry. In general, exposure to a mixture of metals reduced accumulation of single metals in target organs. Interestingly, exposure to mixtures of metals with Pb and/or As increased the concentration of these metals specifically in the liver. The findings from this study indicate that exposure to mixtures of toxic heavy metals may alter significantly the distribution and accumulation of these metals in target organs and tissues.

Disposition of methylmercury over time in a 75% nephrectomized rat model.

Chronic kidney disease (CKD) is a highly relevant clinical condition that is characterized by the permanent loss of functional nephrons. Individuals with CKD may exhibit impaired renal clearance, which may alter corporal handling of metabolites and xenobiotics. Methylmercury (MeHg) is an important environmental toxicant to which humans are exposed to on a regular basis. Given the prevalence of CKD and ubiquitous presence of MeHg in the environment, it is important to understand how mercuric ions are handled in patients with CKD. Therefore, the purpose of the current study was to characterize the disposition of MeHg over time in a rat model of CKD (i.e., 75% nephrectomized (NPX) rats). Control and NPX rats were exposed intravenously (iv) to a non-nephrotoxic dose of MeHg (5 mg/kg) once daily for1, 2, or 3 d and the amount of MeHg in organs, blood, urine, and feces determined. The accumulation of MeHg in kidneys and blood of controls was significantly greater than that of NPX animals. In contrast, MeHg levels in brain and liver of controls were not markedly different from corresponding NPX rats. In all organs examined, accumulation of MeHg increased over the course of exposure, suggesting that urinary and fecal elimination are not sufficient to fully eliminate all mercuric ions. The current findings are important in that the disposition of mercuric ions in rats with normal renal function versus renal insufficiency following exposure to MeHg for a prolonged period differ and need to be taken into account with respect to therapeutic management.

Pregnancy Alters Renal and Blood Burden of Mercury in Females.

Methylmercury (CH3Hg+), a common environmental toxicant, has serious detrimental effects in numerous organ systems. We hypothesize that a significant physiological change, like pregnancy, can alter the disposition and accumulation of mercury. To test this hypothesis, pregnant and non-pregnant female Wistar rats were exposed orally to CH3Hg+. The amount of mercury in blood and total renal mass was significantly lower in pregnant rats than in non-pregnant rats. This finding may be due to expansion of plasma volume in pregnant rats and dilution of mercury, leading to lower levels of mercury in maternal blood and kidneys.

MRP2 and the Transport Kinetics of Cysteine Conjugates of Inorganic Mercury.

Human exposure to mercuric species occurs regularly throughout the world. Mercuric ions may accumulate in target cells and subsequently lead to cellular intoxication and death. Therefore, it is important to have a thorough understanding of how transportable species of mercury are handled by specific membrane transporters. The purpose of the current study was to characterize the transport kinetics of cysteine (Cys)-S-conjugates of inorganic mercury (Cys-S-Hg-S-Cys) at the site of the multidrug resistance-associated transporter 2 (MRP2). In order to estimate the maximum velocity (V max) and Michaelis constant (K m) for the uptake of Cys-S-Hg-S-Cys mediated by MRP2, in vitro studies were carried out using radioactive Cys-S-Hg-S-Cys (5 µM) and inside-out membrane vesicles made from Sf9 cells transfected with MRP2. The V max was estimated to be 74.3 ± 10.1 nmol mg protein-1 30 s-1 while the K m was calculated to be 63.4 ± 27.3 µM. In addition, in vivo studies were utilized to measure the disposition of inorganic mercury (administered dose 0.5 µmol kg-1 in 2 mL normal saline) over time in Wistar and TR¯ (Mrp2-deficient) rats. These studies measured the disposition of mercuric ions in the kidney, liver, and blood. In general, the data suggest that the initial uptake of mercuric conjugates into select target cells is rapid followed by a period of slower uptake and accumulation. Overall, the data indicate that MRP2 transports Cys-S-Hg-S-Cys in a manner that is similar to that of other MRP2 substrates.

Oral exposure of pregnant rats to toxic doses of methylmercury alters fetal accumulation.

Methylmercury (CH3Hg+) is an environmental toxicant that may lead to significant pathologies in exposed individuals. The current study assessed the disposition and toxicological effects of 2.5 or 7.5mgkg-1 CH3Hg+, conjugated to cysteine (Cys; Cys-S-CH3Hg) and administered orally to pregnant and non-pregnant Wistar and TR- rats. Rats were euthanized on gestational day 20 and the content of mercury in each fetus, amniotic sac, and placenta was determined. The brain, liver, and kidneys were removed from each fetus for estimation of mercury content. From the dams, a sample of blood, kidneys, liver, and brain were removed at the time of euthanasia. The findings from this study indicate that pregnancy leads to significant changes in the handling of mercuric ions, particularly in the liver. Furthermore, there are significant differences in the handling of non-nephrotoxic and nephrotoxic doses of Cys-S-CH3Hg by maternal and fetal organs.

Compensatory Renal Hypertrophy and the Uptake of Cysteine S-Conjugates of Hg2+ in Isolated S2 Proximal Tubular Segments.

Chronic kidney disease is characterized by a progressive and permanent loss of functioning nephrons. In order to compensate for this loss, the remaining functional nephrons undergo significant structural and functional changes. We hypothesize that luminal uptake of inorganic mercury (Hg2+), as a conjugate of cysteine (Cys; Cys-S-Hg-S-Cys), is enhanced in S2 segments of proximal tubules from the remnant kidney of uninephrectomized (NPX) rabbits. To test this hypothesis, we measured uptake and accumulation of Cys-S-Hg-S-Cys in isolated perfused S2 segments of proximal tubules from normal (control) and NPX rabbits. The remnant kidney in NPX rabbits undergoes significant hypertrophy during the initial 3 weeks following surgery. Tubules isolated from NPX rabbits were significantly larger in diameter and volume than those from control rabbits. Moreover, real-time PCR analyses of proximal tubules indicated that the expression of selected membrane transporters was greater in kidneys of NPX animals than in kidneys of control animals. When S2 segments from control and NPX rabbits were perfused with cystine or Cys-S-Hg-S-Cys, we found that the rates of luminal disappearance and tubular accumulation of Hg2+ were greater in tubules from NPX animals. These increases were inhibited by the addition of various amino acids to the perfusate. Taken together, our data suggest that hypertrophic changes in proximal tubules lead to an enhanced ability of these tubules to take up and accumulate Hg2.

Compensatory renal hypertrophy and the handling of an acute nephrotoxicant in a model of aging.

Aging often results in progressive losses of functioning nephrons, which can lead to a significant reduction in overall renal function. Because of age-related pathological changes, the remaining functional nephrons within aged kidneys may be unable to fully counteract physiological and/or toxicological challenges. We hypothesized that when the total functional renal mass of aged rats is reduced by 50%, the nephrons within the remnant kidney do not fully undergo the functional and physiological changes that are necessary to maintain normal fluid and solute homeostasis. We also tested the hypothesis that the disposition and handling of a nephrotoxicant are altered significantly in aged kidneys following an acute, 50% reduction in functional renal mass. To test these hypotheses, we examined molecular indices of renal cellular hypertrophy and the disposition of inorganic mercury (Hg(2+)), a model nephrotoxicant, in young control, young uninephrectomized (NPX), aged control and aged NPX Wistar rats. We found that the process of aging reduces the ability of the remnant kidney to undergo compensatory renal growth. In addition, we found that an additional reduction in renal mass in aged animals alters the disposition of Hg(2+) and potentially alters the risk of renal intoxication by this nephrotoxicant. To our knowledge, this study represents the first report of the handling of a nephrotoxicant in an aged animal following a 50% reduction in functional renal mass.

Disposition of inorganic mercury in pregnant rats and their offspring.

Environmental toxicants such as methylmercury have been shown to negatively impact fetal health. Despite the prevalence of inorganic mercury (Hg(2+)) in the environment and the ability of methylmercury to biotransform into Hg(2+), little is known about the ability of Hg(2+) to cross the placenta into fetal tissues. Therefore, it is important to understand the handing and disposition of Hg(2+) in the reproductive system. The purpose of the current study was to assess the disposition and transport of Hg(2+) in placental and fetal tissues, and to test the hypothesis that acute renal injury in dams can alter the accumulation of Hg(2+) in fetal tissues. Pregnant Wistar rats were injected intravenously with 0.5 or 2.5 µmol kg(-1) HgCl2 for 6 or 48 h and the disposition of Hg(2+) was measured. Accumulation of Hg(2+) in the placenta was rapid and dose-dependent. Very little Hg(2+) was eliminated during the initial 48 h after exposure. When dams were exposed to the low dose of HgCl2, fetal accumulation of Hg(2+) increased between 6h and 48 h, while at the higher dose, accumulation was similar at each time point. Within fetal organs, the greatest concentration of Hg(2+) (nmol/g) was localized in the kidneys, followed by the liver and brain. A dose-dependent increase in the accumulation of Hg(2+) in fetal organs was observed, suggesting that continued maternal exposure may lead to increased fetal exposure. Taken together, these data indicate that Hg(2+) is capable of crossing the placenta and gaining access to fetal organs in a dose-dependent manner.

Toxicological significance of renal Bcrp: Another potential transporter in the elimination of mercuric ions from proximal tubular cells.

Secretion of inorganic mercury (Hg(2+)) from proximal tubular cells into the tubular lumen has been shown to involve the multidrug resistance-associated protein 2 (Mrp2). Considering similarities in localization and substrate specificity between Mrp2 and the breast cancer resistance protein (Bcrp), we hypothesize that Bcrp may also play a role in the proximal tubular secretion of mercuric species. In order to test this hypothesis, the uptake of Hg(2+) was examined initially using inside-out membrane vesicles containing Bcrp. The results of these studies suggest that Bcrp may be capable of transporting certain conjugates of Hg(2+). To further characterize the role of Bcrp in the handling of mercuric ions and in the induction of Hg(2+)-induced nephropathy, Sprague-Dawley and Bcrp knockout (bcrp(-/-)) rats were exposed intravenously to a non-nephrotoxic (0.5 µmol · kg(-1)), a moderately nephrotoxic (1.5 µmol · kg(-1)) or a significantly nephrotoxic (2.0 µmol · kg(-1)) dose of HgCl2. In general, the accumulation of Hg(2+) was greater in organs of bcrp(-/-) rats than in Sprague-Dawley rats, suggesting that Bcrp may play a role in the export of Hg(2+) from target cells. Within the kidney, cellular injury and necrosis was more severe in bcrp(-/-) rats than in controls. The pattern of necrosis, which was localized in the inner cortex and the outer stripe of the outer medulla, was significantly different from that observed in Mrp2-deficient animals. These findings suggest that Bcrp may be involved in the cellular export of select mercuric species and that its role in this export may differ from that of Mrp2.

Novel Hg2+-induced nephropathy in rats and mice lacking Mrp2: evidence of axial heterogeneity in the handling of Hg2+ along the proximal tubule.

The role of the multi-resistance protein 2 (Mrp2) in the nephropathy induced by inorganic mercuric mercury (Hg(2+)) was studied in rats (TR(-)) and mice (Mrp2(-/-)), which lack functional Mrp2, and control animals. Animals were exposed to nephrotoxic doses of HgCl2. Forty-eight or 24 hours after exposure, tissues were harvested and analyzed for Hg content and markers of injury. Histological analyses revealed that the proximal tubular segments affected pathologically by Hg(2+) were significantly different between Mrp2-deficient animals and controls. In the absence of Mrp2, cellular injury localized almost exclusively in proximal tubular segments in the subcapsular (S1) to midcortical regions (early S2) of the kidney. In control animals, cellular death occurred mainly in the proximal tubular segments in the inner cortex (late S2) and outer stripe of the outer medulla (S3). These differences in renal pathology indicate that axial heterogeneity exists along the proximal tubule with respect to how mercuric ions are handled. Total renal and hepatic accumulation of mercury was also greater in animals lacking Mrp2 than in controls, indicating that Mrp2 normally plays a significant role in eliminating mercuric ions from within proximal tubular cells and hepatocytes. Analyses of plasma creatinine, BUN, and renal expression of Kim-1 and Ngal tend to support the severity of the nephropathies detected histologically. Collectively, our findings indicate that a fraction of mercuric ions is normally secreted by Mrp2 in early portions of proximal tubules into the lumen and then is absorbed downstream in straight portions, where mercuric species typically induce toxic effects.

Aging and the disposition and toxicity of mercury in rats.

Progressive loss of functioning nephrons, secondary to age-related glomerular disease, can impair the ability of the kidneys to effectively clear metabolic wastes and toxicants from blood. Additionally, as renal mass is diminished, cellular hypertrophy occurs in functional nephrons that remain. We hypothesize that these nephrons are exposed to greater levels of nephrotoxicants, such as inorganic mercury (Hg(2+)), and thus are at an increased risk of becoming intoxicated by these compounds. The purpose of the present study was to characterize the effects of aging on the disposition and renal toxicity of Hg(2+) in young adult and aged Wistar rats. Paired groups of animals were injected (i.v.) with either a 0.5µmol·kg(-1) non-nephrotoxic or a 2.5µmol·kg(-1) nephrotoxic dose of mercuric chloride (HgCl2). Plasma creatinine and renal biomarkers of proximal tubular injury were greater in both groups of aged rats than in the corresponding groups of young adult rats. Histologically, evidence of glomerular sclerosis, tubular atrophy, interstitial inflammation and fibrosis were significant features of kidneys from aged animals. In addition, proximal tubular necrosis, especially along the straight segments in the inner cortex and outer stripe of the outer medulla was a prominent feature in the renal sections from both aged and young rats treated with the nephrotoxic dose of HgCl2. Our findings indicate 1) that overall renal function is significantly impaired in aged rats, resulting in chronic renal insufficiency and 2) the disposition of HgCl2 in aging rats is significantly altered compared to that of young rats.