Rat kidney function related to tissue glutathione levels
Abstract
Rat renal function was evaluated during acute depletion of glutathione (GSH) produced by different doses of diethyl-maleate (DEM). Significant alterations in renal function were observed when the GSH level diminished. The replenishment of GSH and the restoration of renal function were also investigated at various times after the injection. Similar time courses were observed of both the GSH level and renal functions, but the former was shortest. This suggests that the restoration to normal of GSH renal content was necessary in order to regain appropriate kidney function. Furthermore, the fact that impairment of sodium excretion occurred simultaneously with GSH depletion may be considered as evidence of the first event in GSH protective action. It may be hypothetized that the thick ascending limb is the principal renal target for this deficiency.
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Urinary concentrating mechanism and Aquaporin-2 abundance in rats chronically treated with aluminum lactate
2006, ToxicologyThe aim of this work was to study the effects of chronic administration of aluminum (Al) on the urinary concentrating and diluting mechanisms in the distal tubules and collecting ducts. Male Wistar rats were chronically treated with aluminum lactate for 12 weeks (0.575 mg Al/100 g of body weight, i.p., three times per week). After 12 weeks, renal function of control and Al-treated rats was evaluated by clearance techniques. To study urinary concentrating mechanisms, renal function was also measured in control and Al-treated rats deprived of water, after the administration of desmopressin (vasopressin agonist) and after the infusion of hypertonic saline at increasing infusion rates. Sodium and water balance were impaired. We found decreased urinary concentrating ability in situations in which endogenous (thirst or infusion of hypertonic saline) or exogenous plasma antidiuretic hormone was increased. Solute-free water formation, measured during the infusion of hypotonic saline showed normal transport in the thick ascending limb. Aquaporin-2 (AQP2) expression was measured by Western blot to evaluate water permeability in collecting ducts. We found that Al produced downregulation of AQP2 in plasma membranes and intracellular vesicles, that could account for the impaired water handling. Administration of desmopressin increased AQP2 in plasma membranes, suggesting that Al did not impair trafficking of this protein, but could interfere with AQP2 synthesis.
Alterations of the renal function and oxidative stress in renal tissue from rats chronically treated with aluminium during the initial phase of hepatic regeneration
2005, Journal of Inorganic BiochemistryVarious indices of renal functions during the early stage of hepatic injury were studied in rats chronically treated with aluminum (Al) lactate. Tubular and hemodynamic parameters were analyzed four days after producing a 65% partial hepatectomy (PH). Water and sodium balances were also studied. Oxidative stress and the activity of Na–K–ATPase were determined in renal tissue. The rats were distributed in four groups: control, Al, PH, Al + PH. Al did not modify the hemodynamic renal functions and the PH-group reduced the glomerular filtrate rate (GFR). The Al + PH group presented a decrease in the renal blood flow and accentuated the GFR fall as compared with PH. The fractional excretion (FE) of water and sodium increased in the PH group. The rats chronically treated with Al and then submitted to the PH protocol developed a further increase in FE of water but a reduction in FE of sodium. Both PH and Al promoted an increase in the aldosterone. PH and Al induced a similar increase of the lipoperoxidation status with reduction of glutathione (GSH) and the activity of glutathione peroxidase (GSH-Px). The data indicated that Al is an inhibitor of catalase. The GSH and GSH-Px activity in the Al + PH group demonstrated a synergic effect of Al and PH. This work demonstrates that rats treated chronically with Al and submitted to another injury (such as hepatic damage) can aggravate renal functions, probably by increasing the oxidative state, at least in kidneys.
Effects of gender on the pharmacokinetics of drugs secreted by the renal organic anions transport systems in the rat
2002, Pharmacological ResearchThe importance of considering sex differences in drug handling studies was admitted recently. The present work evaluates the sex influences on the pharmacokinetics of para-aminohippuric acid (PAH), the reference substance for the renal organic anion transports systems, and furosemide (FS), a standard loop diuretic which is also a substrate for this transport system. Female rats displayed a lower PAH and FS systemic clearance, and a lower value of the elimination rate microconstant from the central compartment for both drugs. These results may be explained by the diminution of the renal clearance of both PAH and FS observed in females. In summary, sex modifies the pharmacokinetics of organic anions. Although additional experimental work must be done to bridge the gap between studies using animals and humans, the reported experimental observations may have potentially important pharmacological implications. So, caution must be exercised in administering drugs like organic anions to females.
Formation of 8-hydroxydeoxyguanosine in rat kidney DNA after administration of N-ethyl-N-hydroxyethylnitrosamine
1998, Cancer LettersN-Ethyl-N-hydroxyethylnitrosamine (EHEN) is known to induce renal and liver tumors in rodents. Recent reports have indicated the formation of 8-hydroxydeoxyguanosine (8-OHdG), an oxidative DNA product, induced by various carcinogens. In the present study, to examine whether oxygen radicals are involved in tumorigenesis induced by EHEN, we investigated the formation and localization of 8-OHdG in kidney, liver and lung of rats. The effects of reduced glutathione (GSH) and diethylmaleate on these responses were also studied. Multiple doses of EHEN administrations (250, 500 or 750 mg/kg, i.p.) resulted in a significant elevation of the 8-OHdG level in kidney DNA in a dose-dependent manner and the formation of 8-OHdG reached the maximal level at 1–2 h after EHEN injection and recovered to the control level at 4 h. On the other hand, no increase in the 8-OHdG level was observed in the DNA of liver and lung. Combined pre- and post-treatment of rats with 2×800 mg/kg of GSH i.p. inhibited the elevation of the 8-OHdG level induced by EHEN. Pre-treatment with 0.3 ml/kg of diethylmaleate i.p. increased the formation of 8-OHdG. In the immunohistochemical examinations of rats treated with EHEN (750 mg/kg, i.p.), nuclear expression of 8-OHdG was detected in the epithelial cells of renal cortex, while no induction was observed in liver and lung. These findings suggest that the formation of 8-OHdG by active oxygen species may be an important factor in the initiation of EHEN-induced kidney carcinogenesis.
Pathways of glutathione metabolism and transport in isolated proximal tubular cells from rat kidney
1996, Biochemical PharmacologyCellular uptake and metabolism of exogenous glutathione (GSH) in freshly isolated proximal tubular (PT) cells from rat kidney were examined in the absence and presence of inhibitors of GSH turnover [acivicin, ,R-sulfoximine (BSO)] to quantify and assess the role of different pathways in the handling of GSH in this renal cell population. Incubation of PT cells with 2 or 5 mM GSH in the presence of acivicin/BSO produced 3- to 4-fold increases in intracellular GSH within 10–15 min. These significantly higher intracellular concentrations were maintained for up to 60 min. At lower concentrations of extracellular GSH, an initial increase in intracellular GSH concentrations was observed, but this was not maintained for the 60-min time course. In the absence of inhibitors, intracellular concentrations of GSH increased to levels that were 2- to 3-fold higher than initial values in the first 10–15 min, but these dropped below initial levels thereafter. In both the absence and presence of acivicin/BSO, PT cells catalyzed oxidation of GSH to glutathione disulfide (GSSG) and degradation of GSH to glutamate and cyst(e)ine. Exogenous tert-butyl hydroperoxide oxidized intracellular GSH to GSSG in a concentration-dependent manner and extracellular GSSG was transported into PT cells, but limited intracellular reduction of GSSG to GSH occurred. Furthemore, incubation of cells with precursor amino acids produced little intracellular synthesis of GSH, suggesting that PT cells have limited biosynthetic capacity for GSH under these conditions. Hence, direct uptake of GSH, rather than reduction of GSSG or resynthesis from precursors, may be the primary mechanism to maintain intracellular thiol redox status under toxicological conditions. Since PT cells are a primary target for toxicants, the ability of these cells to rapidly take up and metabolize GSH may serve as a defensive mechanism to protect against chemical injury.
Effect of superoxide dismutase treatment on gentamicin nephrotoxicity in rats
1996, General PharmacologyThe effect of administration of superoxide dismutase (SOD) on gentamicin nephrotoxicity was examined in rats. SOD was administered at a dose of 2000 i.u/kg or 8000 i.u/kg for 10 consecutive days, and nephrotoxicity was induced by daily i.m. injections of gentamicin at a dose of 80 mg/kg during the last 6 days of the experimental period. Gentamicin induced significant increases in plasma creatinine and urea and protein urinary concentrations, and significant decreases in creatinine clearance and kidney cortical alkaline phosphatase activity and reduced glutathione (GSH) concentrations. The antibiotic also produced marked necrosis of the renal proximal tubules. SOD treatment (8000 i.u/kg) reversed most of these variables, indicating that it was effective in ameliorating gentamicin nephrotoxicity. However, at a dose of 2000 i.u./kg it was mostly ineffective.