RESUMO
Chronic kidney disease (CKD) is a progressive disease that affects millions of adults every year. Major risk factors include diabetes, hypertension, and obesity, which affect millions of adults worldwide. CKD is characterized by cellular injury followed by permanent loss of functional nephrons. As injured cells die and nephrons become sclerotic, remaining healthy nephrons attempt to compensate by undergoing various structural, molecular, and functional changes. While these changes are designed to maintain appropriate renal function, they may lead to additional cellular injury and progression of disease. As CKD progresses and filtration decreases, the ability to eliminate metabolic wastes and environmental toxicants declines. The inability to eliminate environmental toxicants such as arsenic, cadmium, and mercury may contribute to cellular injury and enhance the progression of CKD. The present review describes major molecular alterations that contribute to the pathogenesis of CKD and the effects of arsenic, cadmium, and mercury on the progression of CKD.
Assuntos
Arsênio , Mercúrio , Metais Pesados , Insuficiência Renal Crônica , Adulto , Arsênio/toxicidade , Cádmio/toxicidade , Exposição Ambiental/efeitos adversos , Substâncias Perigosas , Intoxicação por Metais Pesados/complicações , Humanos , Mercúrio/toxicidade , Metais Pesados/toxicidade , Insuficiência Renal Crônica/metabolismoRESUMO
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.
Assuntos
Glutationa/metabolismo , Artéria Hepática/metabolismo , Túbulos Renais Proximais/efeitos dos fármacos , Cloreto de Mercúrio/sangue , Cloreto de Mercúrio/metabolismo , Cloreto de Mercúrio/toxicidade , Veia Porta/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Masculino , Ratos , Ratos WistarRESUMO
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⯵mol or 2.0⯵mol·kg-1 HgCl2 (containing radioactive Hg) and organs were harvested after 24â¯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.