Renal glutathione homeostasis in compensatory renal growth
Abstract
Glutathione homeostasis was investigated in unilaterally nephrectomized and sham-operated rats. Following twelve days of compensatory renal growth, it was found that the concentrations of glutathione and glutathione disulfide in representative samples of the entire remnant right kidney from the nephrectomized rats were similar to those found in corresponding samples of the right kidneys from the sham-operated rats. However, since the mass of the remnant right kidneys in the nephrectomized rats was greater than that of the right kidneys from the sham-operated rats, the absolute content of glutathione and glutathione disulfide was greater in the remnant right kidneys of the nephrectomized rats than in the right kidneys of the sham-operated rats. In general, the findings from the present study indicate that the absolute content of glutathione and glutathione disulfide in renal epithelial cells increases in proportion to the increase in mass that results from compensatory renal cellular hypertrophy.
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Mechanisms Involved in the Renal Handling and Toxicity of Mercury
2018, Comprehensive Toxicology: Third EditionOne of the most important factors that determines the dispositional and toxicological fate of environmentally relevant forms of mercury in the body is the strong bonding affinity that exists between mercuric ions and reduced sulfur atoms of certain biomolecules. The formation of unique chemical species by the bonding of inorganic and organic mercuric ions in both extracellular and intracellular compartments of the body turns out to be a crucial part of the mechanisms involved in the handling and toxicity of inorganic and organic mercury in specific target tissues and organs, especially in the liver and kidneys. For example, certain membrane transporters present in renal proximal tubular epithelial cells have been shown to import certain species of mercury formed in extracellularly, while other transporters have been shown to export mercuric species formed in intracellular compartments of these target cells. Interestingly, the specific thiol S-conjugates that gain entry into the intracellular milieu of a target (renal) epithelial cell may not be the same type of thiol S-conjugate that is exported out of the cell. Over the last couple of decades, significant progress has been made in identifying membrane transporters in renal proximal tubular cells that take up and export certain thiol S-conjugates mercury. This chapter not only reviews the advances in understanding the roles of the transporters taking up and exporting endogenously formed species of mercury by renal tubular epithelial cells, but it also reviews some of the more relevant findings pertaining to key intracellular biochemical effects of mercuric ions that likely play a role in intoxicating proximal tubular cells. Moreover, discussion of factors that modify the proximal tubular uptake and subsequent toxicity of mercuric species has also been included.
Renal Handling and Toxicity of Mercury
2010, Comprehensive Toxicology, Second EditionMercury is a unique heavy metal that can exist in the environment in several physical and chemical forms, including elemental mercury, which is a liquid at room temperature. All forms of mercury express some form of toxic effects in target organs, especially in the kidneys. Interestingly, the epithelial cells lining the straight portions of renal proximal tubules are among the most vulnerable to the toxic effects of mercury. The biological and toxicological activity of mercurous and mercuric ions can be defined largely by chemical bonding with critical nucleophilic sites in and around target cells. Due to the high bonding affinity between mercuric ions and sulfur-reduced atoms, particular interest is paid to the interactions that occur between mercuric ions and thiol group(s) of proteins, peptides, and amino acids. Chemical interactions between mercuric ions and sulfhydryl groups in molecules of albumin, metallothionein, glutathione, and cysteine have been implicated in the mechanisms participating in the uptake, accumulation, transport, and toxicity of mercuric ions in the renal proximal tubule. Numerous factors, both within and outside the intracellular compartment of proximal tubular epithelial cells, influence greatly the susceptibility of these target cells to the injurious effects of mercury. These very factors serve as the theoretical basis for most of the currently employed therapeutic strategies used for mercury poisoning in humans. This chapter provides a brief update on the current body of knowledge regarding the mechanisms involved in the renal cellular uptake, accumulation, elimination, and toxicity of mercury.
Activities of enzymes involved in renal cellular glutathione metabolism after uninephrectomy in the rat
1994, Archives of Biochemistry and BiophysicsThe renal concentration of GSH increases after a significant reduction in renal mass and compensatory renal growth. To test the hypothesis that this increase is due to induction of GSH synthesis, the activities of γ-glutamylcysteine synthetase, other GSH-dependent enzymes, and selected enzymes involved in cellular energetics were measured in freshly isolated proximal tubular (PT) and distal tubular (DT) cells from male Sprague-Dawley rats that underwent uninephrectomy and compensatory renal growth or from sham-operated rats. Significant increases in cellular content of protein without increases in intracellular content of DNA, in both PT and DT cells, confirmed that cellular hypertrophy had occurred. γ-Glutamylcysteine synthetase activity increased significantly in PT cells, but not in DT cells, as a result of compensatory cellular hypertrophy, indicating that the effects of cellular hypertrophy on GSH synthesis occurred exclusively in the proximal tubule. Hypertrophy in PT cells, but not in DT cells, was associated with significant increases in activities of glutathione disulfide reductase, both Mg2+-dependent and (Na+ + K+)-stimulated ATPases, succinate:cytochrome c oxidoreductase, and lactate dehydrogenase. Results from this study demonstrate that compensatory hypertrophy occurs in both PT and DT cells and that effects on GSH metabolism and cellular energetics associated with compensatory hypertrophy are more pronounced in PT cells than in DT cells. The findings also support our hypothesis that GSH synthesis is induced in the proximal tubule during compensatory hypertrophy. The increase in GSH synthesis may be an adaptive response to protect against oxidative stress caused by increases in mitochondrial metabolism.
Altered intrarenal accumulation of mercury in uninephrectomized rats treated with methylmercury chloride
1992, Toxicology and Applied PharmacologyWe tested the hypothesis that the intrarenal accumulation of mercury in rats treated with methylmercury is altered significantly as a result of unilateral nephrectomy and compensatory renal growth. Renal accumulation of mercury was evaluated by radioisotopic techniques in both uninephrectomized (NPX) and sham-operated (SO) rats 1, 2, and 7 days after the animals received a nonnephrotoxic intravenous dose of methylmercury chloride (5 mg/kg Hg). At all times studied after the injection of the dose of methylmercury, the renal accumulation of mercury (on a per gram kidney basis) was significantly greater in the NPX rats than that in the SO rats. The increased accumulation was due to a specific increase in the accumulation of mercury in the outer stripe of the outer medulla. Renal cortical accumulation of mercury was similar in both the NPX and SO rats. The percentage of the administered dose of mercury that was present in the total renal mass of the NPX and SO rats ranged between 5 and 15, depending on the day that the renal accumulation was studied. Approximately 40–50% of the total renal burden of mercury in both the NPX and SO rats was in the inorganic form. However, only less than 1% of the mercury in blood was in the inorganic form at the three times accumulation was studied. Very little mercury was excreted in the urine by either the NPX or SO rats. Only about 2 to 3% of the administered dose of mercury was excreted in the urine in 7 days. By contrast, the cumulative fecal excretion of mercury over 7 days was substantial in the NPX and SO rats, and significantly more mercury was excreted in the feces by the NPX rats (about 19% of the dose) than by that in the SO rats (about 16% of the dose). In conclusion, our findings indicate that unilateral nephrectomy and compensatory renal growth cause a significant increase in the accumulation of mercury in the renal outer stripe of the outer medulla in rats exposed to methylmercury. In addition, the findings indicate that the fecal excretion of mercury is also significantly increased.
The effects of unilateral nephrectomy and compensatory renal growth on renal metallothionein metabolism were evaluated in the present study. In rats, the renal content of metallothionein increased in proportion to the increase in renal mass after unilateral nephrectomy and compensatory renal growth. However, when zinc was used to induce the synthesis of renal metallothionein, the remant kidney in uninephrectomized (NPX) rats produced significantly greater amounts of metallothionein on a per gram kidney basis than a normal kidney in sham-operated (SO) rats. In both NPX and SO rats, zinc pretreatment caused metallthionein synthesis to increase primarily in the renal cortex aand outer stripe of the outer medulla. Zinc pretreatment also changed the pattern for the intrarenal accumulation of inorganic mercury in NPX rats. After pretreatment with zinc, the accumulation of inorganic mercury predominated in the renal cortex rather than in theouter stripe of the outer medulla in the NPX rats. In addition, both NPX and SO rats were afforded complete protection against the nephrotoxic effects of a low, toxic dose of inorganic mercury when they were pretreated with inorganic zinc. The protection is postulated to be related to the alteration in the pattern of renal accumulation of inorganic mercury. In conclusion, the capacity to synthesize metallothionein increases significantly in rats after they have undergone unilateral nephrectomy and compensatory renal growth. The increased capacity of the remant kidney to synthesize metallothionein may involve adaptive changes both in trancriptional and/or translationalontrols of metallothionein synthesis.
In the present study we examined the effects of zinc pretreatment (to induce the renal synthesis of metallothionein) on the renal accumulation and intrarenal distribution of inorganic mercury in uninephrectomized (NPX) and sham-operated (SO) rats 24 h after the animals were given a 0.75, 1.0 or 1.5 μmol/kg intravenous (i.v.) dose of inorganic mercury. We also examined the effects of zinc pretreatment on the nephropathy induced by the three doses of inorganic mercury. Zinc was administered at a dose of 306 μmol/kg (20 mg/kg) subcutaneously (s.c.) in the form of zinc sulfate once daily for 2 consecutive days prior to the administration of inorganic mercury. Following zinc pretreatment, the renal accumulation of injected inorganic mercury increased in both NPX and SO rats treated with the three doses of inorganic mercury, but the increase was significantly greater in the NPX rats. The enhanced accumulation of mercury was associated with an altered pattern in the intrarenal distribution of mercury, particularly in the NPX rats. The increased renal accumulation of mercury in both the NPX and SO rats was due primarily to its increase in the renal cortex. We have recently found that the synthesis of metallothionein in the renal cortex increases in NPX and SO rats given zinc. Therefore, it appears that there is a relationship between the content of preinduced cellular metallothioein in the cortex and the content of mercury that accumulates in the cortex. Zinc pretreatment also prevented the nephropathy induced by the three doses of inorganic mercury from occurring in both the NPX and SO rats. We propose that some of the protection may be related to the altered intrarenal accumulation and distribution of mercury that occurs after pretreatment with zinc. Hepatic accumulation of mercury also increased in both groups of rats, but increase again was significantly greater in the NPX rats. Our findings show clearly that a significant reduction in renal mass alters the hepatic and renal accumulation of mercury when zinc pretreatment is used to induce the renal and hepatic synthesis of metallothinein. In addition, our findings show that zinc pretreatment protects both normal and remnant kidneys in rats from the nephrotoxic effects of inorganic mercury.