Klaus Winnefeld

LLU-α, an endogenous metabolite of γ-tocopherol, is more effective against metal nephrotoxicity in rats than γ-tocopherol ☆

Antioxidants of the vitamin E family have protective effects against metal toxicity. We examined the protective effect of racemic LLU-α [2,7,8-trimethyl-2-(carboxyethyl)-6-hydroxychroman] a metabolite of γ-tocopherol, in comparison to the effect of α- and γ-tocopherol in rats treated with sodium dichromate (Cr) or thallium sulfate (Tl). We measured metal nephrotoxicity based on urinary protein excretion and discussed it with respect to the metal concentration in renal tissue. The ranking of antioxidant activity (iron stimulated lipid peroxidation, luminol and lucigenin amplified chemiluminescence) was determined in the following order: α-tocopherol<γ-tocopherol<LLU-α. Pretreatment with LLU-α produced lower chromate nephrotoxicity than α- or γ-tocopherol, but did not influence Cr concentration in renal tissue. The protective effect of LLU-α against Cr toxicity seemed to be caused by its stronger antioxidant activity in comparison to α- and γ-tocopherol. Pretreatment with LLU-α resulted in lower thallium-induced proteinuria, a lower concentration of Tl in the renal medulla, and higher urinary Tl excretion. Unlike LLU-α, which has been shown to inhibit K+ channels in the apical membrane of the thick ascending limb of Henles loop, we found that γ-tocopherol did not. This finding reaffirmed the similarity between K+ and Tl+ and also explained the significantly decreased Tl concentration in the renal medulla in rats treated with LLU-α. We speculate that the protective effect of LLU-α against Tl nephrotoxicity is caused both by its antioxidant effect and, at least in part, by its ability to decrease Tl concentration as a consequence of inhibited Tl+ uptake through K+ channels. This finding confirmed the similarity between K+ and Tl+ and also explained the significantly decreased Tl concentration in the renal medulla in rats treated with LLU-α.

Role of Glutathione for Cisplatin Nephrotoxicity in Young and Adult Rats

Investigations were done in 10- and 55-day-old Wistar rats. Glutathione (GSH) level in kidney was decreased by 8 mmol buthionine sulfoximine (BSO)/100 g BW. There was no effect on the renal function and nephrotoxicity of cisplatin (0.6 mg CP/100 g BW) in adult rats. In young rats BSO treatment was followed by nephrotoxic effects. Pt concentration remained unaffected by BSO in young and adult rats. GSH concentration in kidney was increased by 100 mg acetyl-cysteine (accys)/100 g BW. CP nephrotoxicity was lower in young as well as in adult ac-cys-treated rats. Pt levels in renal tissue were significantly decreased in rats from both age groups. From our results we conclude that the beneficial effect of high GSH concentration in renal tissue on CP nephrotoxicity is the result of decreased Pt concentration in kidney.

Functional and morphological aspects of thallium-induced nephrotoxicity in rats

Until now the effect of thallium (Tl) on renal function has not been investigated systematically. Therefore, the dose (5, 10, 15, 20 mg Tl2SO4/kg body wt., intraperitoneally) and time-dependence of renal damage was investigated in diuresis experiments on conscious rats. Morphology was evaluated after perfusion fixation in situ. Morphologic changes were localized in the thick ascending limb of the loop of Henle, mostly expressed at the 2nd day after Tl administration, which were completely normalized again at the 10th day. Other parameters such as Tl concentration, changes in water content and the activity of Na+/K(+)-ATPase as well as the diuretic effect of furosemide confirmed the Tl effect to be localized in the renal medulla. One single Tl administration is followed by a decrease in glomerular filtration rate (GFR) and urine volume and an increase of proteinuria. Electrolyte excretion was only slightly changed. All changes were reversible within the 10-day investigation period.

Riboflavin can decrease the nephrotoxic effect of chromate in young and adult rats

The influence of 5 mg vitamin B2/100 g b.wt. (B2, riboflavin) on the nephrotoxic effect of 1 or 2 mg Na2Cr2O7/100 g b.wt. (Cr) was investigated in 55- and 10-day-old rats, respectively. Nephrotoxic effect was evaluated by the determination of urinary volume and protein excretion as well as the concentration of blood urea nitrogen (BUN). The concomitant administration of Cr and B2 only in 55-day-old rats increased the nephrotoxicity shown by enhanced proteinuria and BUN. B2, administered 3 h after Cr, was able to diminish Cr nephrotoxicity significantly in 55- and 10-day-old rats. The effect of B2 on Cr nephrotoxicity could be interpreted not by the stimulatory effect of B2 on GSSG reductase, which was abolished by Cr; but by its antioxidant effect.

Is thallium-induced nephrotoxicity in rats connected with riboflavin and/or GSH? Reconsideration of hypotheses on the mechanism of thallium toxicity

Adult female Wistar rats (Han:Wist) were injected with 2 mg of Tl2SO4 per 100 g body weight. Parameters of nephrotoxicity were urinary volume and protein excretion as well as blood urea nitrogen concentration. Thallium concentrations were determined in renal cortex and medulla.

Ontogenetic Aspects of Thallium‐induced Nephrotoxicity in Rats

The effect of Tl2SO4 (Tl, 20 mg kg−1 body wt.) on renal function was investigated in 10‐ and 20‐day‐old rats. Nephrotoxic effects were evaluated by the determination of glomerular filtration rate, urinary volume, electrolyte and protein excretion, as well as by morphological investigations.

Blutselengehalte nach Konditionierung sowie im Verlauf der Knochenmarktransplantation bei Kindern mit malignen Erkrankungen

Summary□Patients and Results: Prior to bone marrow transplantation (BMT), at the end of the conditioning phase, we found in 42 investigated children with malignant diseases subnormal lowered plasma- and blood selenium levels. Parallel to the diminished selenium status the plasma glutathione peroxidase activity (Gpx) was not reduced as it is in selenium deficiency, but markedly elevated and probably reflecting cytolytic processes. In the group of combined conditioning (fractionated total body irradiation plus chemotherapy) we found significantly more elevated plasma Gpx values in comparison to the only-chemotherapy group. The renal selenium excretion was elevated during the whole observation and could be caused by disturbed tubular function.□ Conclusion: We conclude, that in the situation of BMT a selenium substitution in a dosage of at least 1 to 2 µg Se/kg/d is necessary. Patients’ selenium status should be monitored by analyses of plasma-and blood selenium contents.