Effects of cyclosporin A, gentamicin and furosemide on rat renal function: a lithium clearance study

1. This study applied clearance methods of inulin, lithium, potassium, sodium and para-aminohippuric acid (PAH) for investigation of the effects of cyclosporin A (CyA), furosemide and gentamicin on rat (n = 92) renal function. The drugs were dosed for 2 weeks; CyA 12.5 mg/kg per day, gentamicin 32 mg/kg per day and furosemide 5 mg/kg per day. 2. The questions asked were: could these methods differentiate the effects of drugs with different sites of action, and would gentamicin or furosemide exaggerate the nephrotoxicity of CyA? 3. Furosemide increased sodium clearance (CNa) 74% and fractional sodium clearance (FENa) 105%, while fractional sodium reabsorption in the distal nephron (FDNR) was reduced, compared with placebo-treated controls. 4. Gentamicin reduced CPAH 29% and Cin 37%, while FENa increased 335%. Proximal fractional reabsorption (PFR) and absolute proximal reabsorption (APR) decreased. 5. CyA depressed CPAH 32% and lithium clearance (CLi) 56%, and increased PFR. 6. The effects of CyA and furosemide in reducing renal function were not additive. 7. CyA plus gentamicin reduced CPAH to 35% of the value in untreated controls, equal to 52% of the CPAH of CyA-treated rats; Cin was reduced to 46% of the Cin of CyA-treated rats. 8. Rats given CyA, furosemide and gentamicin had decreased Cin, CPAH and CLi compared with rats given either CyA plus furosemide or gentamicin plus furosemide. 9. Thus, in this investigation of drugs known to have different sites of actions, the differences in renal and tubular function were discernible with the lithium clearance method. 10. The nephrotoxicities of CyA and of gentamicin were additive, while furosemide did not aggravate CyA nephrotoxicity.     

Effects of gemcitabine on cisplatin-induced nephrotoxicity in rats: schedule-dependent study.

The effects of gemcitabine (dFdC) on the lipid peroxidation and kidney histopathology in the nephrotoxicity of an antitumour drug cisplatin (CDDP) were studied in rats. dFdC was administered intraperitoneally (i.p.) at single doses of 90 mgkg(-1) while CDDP was administered i.p. at single doses of 6 mgkg(-1). Both drugs were injected either alone or sequentially in combination. In one case, CDDP preceded dFdC by 4 h and 24 h and in the other case, dFdC preceded CDDP by 4 h and 24 h. Seven days after CDDP administration, the nephrotoxicity was manifested biochemically by elevation of serum creatinine, blood urea nitrogen and an increase in the kidney weight as a percentage of total body weight. In addition, marked decreases in serum albumin and calcium levels were observed. Lipid peroxidation in the kidney was monitored by measuring the malondialdehyde (MDA) production level and kidney glutathione (GSH) content, which were increased and depleted, respectively. Administration of dFdC 4 h and 24 h after CDDP administration did not significantly change the indices of CDDP-induced nephrotoxicity or the kidney platinum concentration levels in comparison with those animals treated with CDDP alone. On the contrary, administration of dFdC 4 h and 24 h prior to CDDP administration significantly aggravated CDDP-induced nephrotoxicity which was manifested by severe increases in the serum creatinine and blood urea nitrogen levels as well as kidney weight as a percentage of total body weight. In addition, kidney tissue showed severe GSH depletion and increases in the MDA production and platinum concentration levels. Moreover, treatment of rats with dFdC 24 h prior to CDDP resulted in much more aggravation of CDDP-induced nephrotoxicity in comparison with those animals treated with dFdC 4 h prior to CDDP. Histopathological examination demonstrated tubular atrophy, tubular necrosis and drug-induced nuclear changes in the CDDP-treated group. However, pretreatment of rats with dFdC 4 h and 24 h prior to CDDP revealed extensive interstitial nephritis, renal tubular atrophy and tubular necrosis with 'sloughing off' of the lining cells, especially with those rats treated with dFdC 24 h prior to CDDP. These results might suggest that administration of dFdC prior to CDDP enhanced the lipid peroxidation in kidney tissue and aggravated CDDP-induced nephrotoxicity.     

Polymeric micellar delivery reduces kidney distribution and nephrotoxic effects of Cyclosporine A after multiple dosing

The aim of this study was to test the ability of poly(ethylene oxide)-b-poly (epsilon-caprolactone) (PEO-b-PCL) micelles to reduce the renal uptake and nephrotoxicity of Cyclosporine A (CyA) after multiple dose administration. Sprague-Dawley rats received CyA i.v. at a dose of 20 mg/kg/day delivered as the commercial formulation (Sandimmune) or polymeric micellar formulation (PM-CyA). Cremophor EL (the solubilizing agent in Sandimmune), unloaded PEO-b-PCL micelles, or normal saline were also administered i.v. to control rats. After 7 days, kidney function was assessed through measurement of creatinine (CLcr) and urea clearances, as well as electrolyte concentrations in plasma. Blood and kidney were collected and assayed for CyA. Sandimmune administration led to decreased CLcr, and increased urea and potassium levels in plasma. In contrast, functional nephrotoxicity with the PM-CyA was not apparent, as the CLcr did not change significantly. The rate of increase in body weight in control rats was 3.1-3.4% per day. Weight gains (1.8% per day) were also noted in the rats given PM-CyA, although the body weight of animals receiving Sandimmune remained constant. Compared to Sandimmune, polymeric micelles reduced kidney uptake of CyA by 2.6-fold, and increased CyA levels in blood by 2.1-fold. The results show a potential for PEO-b-PCL micelles in restricting the nephrotoxicity of CyA.     

Effects of calcineurin inhibitors on pharmacokinetics of mycophenolic acid and its glucuronide metabolite during the maintenance period following renal transplantation

Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF) has been introduced into renal transplant immunosuppressant protocols in combination with calcineurin inhibitors (CNIs) and steroids. This study compared the pharmacokinetic profiles of MPA and its major metabolite MPA glucuronide (MPAG) in combination with tacrolimus (TAC) or cyclosporine (CyA) during the maintenance period (>6 months) following renal transplantation. There was no difference between TAC and CyA-treated groups in MPA plasma concentration before drug administration (C(0)). MPA C(0) in TAC and CyA-treated patients did not differ from that in patients who were not treated with a CNI. In patients treated with a CNI, MPAG C(0) was significantly greater in those treated with CyA compared with TAC. The MPAG/MPA ratio in CyA-treated patients was significantly greater than that in the TAC-treated group. We observed that C(0) of MPA was negatively correlated with that of TAC and CyA. Positive correlation between MPA C(0), MPAG C(0) and serum creatinine was stronger in patients treated with CyA compared with TAC. Our study suggests that CyA, but not TAC, inhibits enterohepatic circulation of MPAG as a secondary excretion pathway, and that renal function makes a major contribution to elimination of MPA and MPAG. We indicate that it may be necessary to estimate biliary excretion of MPAG to avoid the risk of intestinal injury in patients receiving combination therapy with TAC during the maintenance period.     

Role of non-selective adenosine receptor blockade and phosphodiesterase inhibition in cisplatin-induced nephrogonadal toxicity in rats

1. It is well documented that cisplatin (CDDP) treatment increases the expression of adenosine A(1) receptors in both kidney and testes. However, the effect of adenosine at these receptors is controversial. Adenosine A(1) receptors have been documented to be involved in either cytoprotection or aggravation of nephrotoxicity. The aim of the present study was to examine the effect of the non-selective adenosine receptor inhibitor theophylline and the phosphodiesterase inhibitor pentoxifylline on CDDP-induced renal and testicular toxicity. 2. Male Wister rats were divided into six groups. Two control groups received plain drinking water and a third control group received theophylline 0.8 mg/mL in the drinking water for 2 weeks. One group of animals drinking plain water was injected intraperitoneally (i.p.) with pentoxifylline 50 mg/kg per day for 2 weeks. The remaining groups were treated in the same manner and received single dose of CDDP 7 mg/kg, i.p., 1 week after starting theophylline and pentoxifylline treatment and all animals were killed 1 week after CDDP treatment. 3. Rats treated with CDDP developed nephrotoxicity, as demonstrated by increased kidney and testes weight as a percentage of total bodyweight, blood urea nitrogen and serum creatinine levels and decreased serum calcium and albumin levels. In addition, CDDP treatment resulted in an increase in the production of malondialdehyde (MDA) and decreases in total nitrate/nitrite levels, as well as depletion of reduced glutathione (GSH) content and glutathione peroxidase (GPX) activity in both the kidney and testes. Administration of theophylline in the drinking water to CDDP-treated rats resulted in exacerbation of the indices of nephrotoxicity, depletion of GSH content and GPX activity levels, with increased MDA production and platinum accumulation in both the kidney and testes. However, pentoxifylline administration reduced CDDP-induced biochemical changes and reduced platinum accumulation in both organs. Histopathological examination of the kidney revealed that CDDP treatment produced multifocal tubular atrophy, atypical reparative changes of the tubular epithelium and marked tubular necrosis. Animals treated with the theophylline/CDDP combination showed extensive widespread damage with intratubular calcification. However, pentoxifylline treatment ameliorated the overt changes induced by CDDP treatment. 4. Theophylline exacerbates the deleterious effects of CDDP on rat kidney and testes. However, pentoxifylline alleviates CDDP-induced renal and testicular toxicity.     

Enhancement of renal organic base accumulated by potassium dichromate.

N-Methylnicotinamide (NMN) accumulation by renal cortical slices from potassium dichromate-treated rats was not different from control at 30 min of incubation, but was substantially higher when the incubation was continued for 60 min or longer. Intravenous injection of NMN resulted in significantly higher cortex/serum concentration ratios when rats were treated 24 hr earlier with potassium dichromate. Incubation of renal cortical slices under N₂ or at O°C reduced NMN slice-medium ratios to about 1; reincubation under normal conditions returned the slice/medium ratios to normal values in controls but not in dichromate-treated animals. Replacement of drinking water with saline for 5 wk reduced both the dichromate-induced nephrotoxicity and the enhanced uptake of NMN by kidney slices. Concomitant treatment with dimercaprol and dichromate did not reduce dichromate-induced toxicity or enhancement of NMN slice accumulation. Chromium chloride elicited neither nephrotoxicity nor stimulation of NMN uptake. The enhancement of renal NMN accumulation or retention by potassium dichromate appears to be associated with the nephrotoxicity produced by this compound.     

Protective effects of oral arabic gum administration on gentamicin-induced nephrotoxicity in rats.

Arabic gum (AG) is a complex polysaccharide used as suspending agent. It has been widely used by eastern folk medicine practitioners as a restorative agent and is thought to be an excellent curative for renal failure patients. We therefore tested these folkloric claims using a rat model of gentamicin (GM)-induced nephrotoxicity. AG (7.5g 100ml(-1), in drinking water) was administered orally for 8 days concurrently with GM (80mgkg(-1) per day, i.p.). Estimation of urine volume, serum creatinine and urea concentrations, kidney tissue malondialdehyde (MDA) contents and glutathione (GSH) were carried out after the last dose of GM. Kidneys were also examined for histological changes. GM caused a marked nephrotoxicity as evidenced by significant increases in urine volume (295%), serum creatinine (318%) and urea (258%) and a significant decrease in creatinine clearance (Ccr) (26%). Treatment with AG protected the rats from GM-induced nephrotoxicity as evident by normalisation of these parameters. In addition there was about 187% increase in kidney tissue MDA contents above the control with GM treatment. AG totally prevented the GM-induced rise in kidney tissue contents of MDA. Kidney histology of the tissue from GM-treated rats showed necrosis and desquamation of tubular epithelial cells in renal cortex as well as interstitial nephritis. Whereas it was very much comparable to control when AG was co-administered with GM. In conclusion, AG protected the rats from GM-induced nephrotoxicity, possibly, at least in part through inhibition of the production of oxygen free radicals that cause lipid peroxidation.     

Hyperlipidaemia in cisplatin-induced nephrotic rats.

The serum and hepatic lipid concentrations were investigated in rats made nephrotic with a single intraperitoneal injection of cisplatin (6 mg kg(-1) b.wt.). The serum creatinine and urea concentrations were estimated as indices of nephrotoxicity, and the serum total bilirubin level as a liver function test. 3 The fasting serum total cholesterol, triglycerides (TG) and the cholesterol fractions associated with the various lipoproteins, as well as hepatic cholesterol and TG contents were also measured, following 5, 10 and 15 days from the cisplatin treatment. 4 The results revealed that on day 5 both serum creatinine and urea concentrations were significantly (P<0.01) increased, indicating the peak of nephrotoxicity, with no injurious effects on the liver as indicated by the unaltered serum bilirubin concentration. 5 The nephrotoxicity was accompanied by significant elevations in serum total cholesterol and TG concentrations by 49 and 42%, respectively, with significant (P < 0.05) correlations between the serum cholesterol and TG concentrations versus the serum urea (r=0.68 and r=0.60, respectively). Among the estimated lipoproteins, very low density lipoprotein (VLDL) cholesterol was severely increased to more than twofold with no severe changes in LDL- or HDL-cholesterol fractions. On day 5 the liver also showed significant accumulation of TG with no change in the cholesterol content. Animals killed 10 or 15 days post-cisplatin treatment had all the perturbed parameters returned to the normal levels. The present results indicated that rats exposed to a single cisplatin injection exhibit acute reversible nephrosis on day 5 which was accompanied by dyslipidaemia and accumulated liver TG.     

The Effects of Ischemic Postconditioning on Myocardial Function and Nitric Oxide Metabolites Following Ischemia-Reperfusion in Hyperthyroid Rats

Ischemic postconditioning (IPost) could decrease ischemia-reperfusion (IR) injury. It has not yet reported whether IPost is useful when ischemic heart disease is accompanied with co-morbidities like hyperthyroidism. The aim of this study was to examine the effect of IPost on myocardial IR injury in hyperthyroid male rats. Hyperthyroidism was induced with administration of thyroxine in drinking water (12 mg/L) over a period of 21 days. After thoracotomy, the hearts of control and hyperthyroid rats were perfused in the Langendorff apparatus and subjected to 30 minutes global ischemia, followed by 120 minutes reperfusion; IPost, intermittent early reperfusion, was induced instantly following ischemia. In control rats, IPost significantly improved the left ventricular developed pressure (LVDP) and ±dp/dt during reperfusion (p<0.05); however it had no effect in hyperthyroid rats. In addition, hyperthyroidism significantly increased basal NO_x (nitrate+nitrite) content in serum (125.5±5.4 µmol/L vs. 102.8±3.7 µmol/L; p< 0.05) and heart (34.9±4.1 µmol/L vs. 19.9±1.94 µmol/L; p<0.05). In hyperthyroid groups, heart NO_x concentration significantly increased after IR and IPost, whereas in the control groups, heart NO_x were significantly higher after IR and lower after IPost (p< 0.05). IPost reduced infarct size (p<0.05) only in control groups. In hyperthyroid group subjected to IPost, aminoguanidine, an inducible nitric oxide (NO) inhibitor, significantly reduced both the infarct size and heart NO_x concentrations. In conclusion, unlike normal rats, IPost cycles following reperfusion does not provide cardioprotection against IR injury in hyperthyroid rats; an effect that may be due to NO overproduction because it is restored by iNOS inhibition.     

Influence of metal cations on plasma trough concentration of mycophenolic Acid and its glucuronide in tacrolimus-treated and cyclosporine-treated kidney transplant recipients

The aim of this study was to evaluate the plasma trough concentrations (C(0)) of mycophenolic acid (MPA) and its major metabolite MPA 7-O-glucuronide (MPAG) in metal cation (MC)(-) (non-treated) and MC(+) (co-treated) patients who received tacrolimus (Tac) or cyclosporine (CyA). Fifty-nine Japanese stable kidney transplant recipients receiving immunosuppressive regimens containing mycophenolate mofetil (MMF) and a calcineurin inhibitor (CNI) were included in this study. Seven in the 25 patients receiving Tac and 8 in the 34 patients receiving CyA were treated with concomitant MCs administration. Multiple regression analysis revealed that concomitant MCs and CyA administration influenced MPA C(0). Their standardized partial regression coefficients were -0.29 and -0.41, respectively. Stratified analysis based on CNI treatment revealed that MPA C(0) decreased significantly by 56% with concomitant MCs administration in Tac-treated patients. There was no significant difference in MPA C(0) between the MC(-) and MC(+) groups in CyA-treated patients. With respect to MPAG C(0), MC(+) group tended to be lower by 26% than MC(-) group in Tac-treated patients. There was no significant difference in MPAG C(0) between the MC(-) and MC(+) groups in CyA-treated patients. Concomitant MCs administration did not affect the C(0) ratio of MPAG to MPA in either Tac- or CyA-treated patients. In conclusion, MCs co-administration decrease MPA C(0) in patients receiving Tac and may cause lower MPA exposure. There are little pharmacokinetic interactions between MMF and concomitant MCs in CyA-treated patients.     

Trigonelline ameliorates diabetic hypertensive nephropathy by suppression of oxidative stress in kidney and reduction in renal cell apoptosis and fibrosis in streptozotocin induced neonatal diabetic (nSTZ) rats

Oxidative stress and apoptotic cell death in kidney have been suggested as contributing factors in the development and complication of diabetes especially in diabetic nephropathy (DN). This study investigated the effects of trigonelline (TG) on the renal functional, morphological changes and renal apoptosis in neonatal diabetic rats, a model of non-insulin-dependent diabetes mellitus. Diabetes mellitus was induced in one day old neonatal Wistar rat pups by an intraperitoneal (i.p.) injection of streptozotocin (STZ) (50 mg/kg) and monitored for 16 weeks thereafter. The diabetic rats were divided as follows: the nSTZ diabetic group, the TG (50 mg/kg) treated diabetic group, and the TG (100 mg/kg) treated diabetic group. The age matched nondiabetic group received an injection of citrate buffer (0.1 M, pH 4.5). At the end kidney samples were taken for light microscopic examinations. The levels of serum creatinine and BUN were significantly low in TG (100 mg/kg) treated diabetic rats. Glomerular filtration rate was improved in TG treated rats. The activities of antioxidant enzyme and membrane bound enzyme were decreased and the levels of tumor necrotic factor (TNF-α) and hydroxyproline content were increased in renal tissues of the diabetic group. TG (100 mg/kg/day) treatment for a period of 4 weeks showed significant ameliorative effects on all the biochemical parameters studied. Biochemical findings were supported by histological studies. The degenerative changes in kidney tissue and fibrosis were alleviated in the TG treated groups. These results suggested that TG might have a significant role in alleviating kidney damage in nSTZ-diabetic rats.     

Nephrotoxicity of hexachloro-1:3-butadiene in the rat: The effect of age,sex, and strain

Adult male rats are less susceptible to hexachloro-1:3-butadiene-induced nephrotoxicity than adult female and young male rats. A single dose of 50 mg/kg hexachloro-1:3-butadiene (HCBD) ip in adult Alderley Park (Wistar-derived) females produced marked renal tubular necrosis and an increased plasma urea by 24 hr. Young male rats were also more susceptible to HCBD-induced nephrotoxicity; a dose of 25 mg/kg produced marked tubular necrosis and an increased plasma urea in 21-day-old rats, while a dose of 200 mg/kg was required to produce a similar response in adult males. p-Aminohippurate accumulation by thin slices of renal cortex from rats treated 24 hr previously with HCBD was reduced in adult but not in young male rats. HCBD was more toxic to young male rats (21 and 29 days old, LD50 57 and 96 mg/kg. respectively) than to adult males (7 weeks old, LD50 360 mg/kg). HCBD administration produced a more marked nephrotoxicity in 21-day-old rats treated with phenobarbital in their drinking water for 7 days than in rats of the same age not treated with phenobarbital. Associated with the increased susceptibility of female rats, renal nonprotein sulfhydryl content (NP-SH) was decreased in female but not in male rats 4 hr after HCBD administration. This decrease suggests conjugation of HCBD by the female rat kidney. The sex and age differences observed in nephrotoxicity due to HCBD are probably related to differences in hepatic and renal enzymes responsible for the detoxification and/or activation of HCBD. Fischer 344 rats were slightly more susceptible and Long Evans rats slightly less susceptible than the Alderley Park strain to HCBD-induced nephrotoxicity, although the differences were not as marked as those seen with age and sex.     

Contribution of acetone and osmotic-diuresis by streptozotocin-induced diabetes in attenuation of cephaloridine nephrotoxicity.

Previous studies have indicated that cephaloridine nephrotoxicity was reduced in streptozotocin (STZ)-induced diabetic rats. Experiments were performed to investigate if a shorter duration of diabetes would reduce cephaloridine nephrotoxicity. Studies were also conducted to examine the contribution of osmotic diuresis and ketone accumulation to the mechanism for reduced toxicity. Male Fischer 344 (F344) rats were injected with 30 mg/kg STZ or vehicle. Seven days after STZ or vehicle administration, the animals were treated (i.p.) with 1500 mg/kg cephaloridine. Increased kidney weight, blood urea nitrogen (BUN) level and decreased renal cortical slice accumulation of p-aminohippurate (PAH) and tetraethyl-ammonium (TEA) were measured in the normoglycemic group. No differences in renal function were detected between diabetic groups treated with cephaloridine or vehicle (PFC). Pretreatment of euglycemic rats with 0 or 10% dextrose in the drinking water and by oral gavage failed to prevent the renal damage produced by 1500 mg/kg cephaloridine despite glucosuria and urine output comparable to diabetic animals. However, dextrose-diuresis afforded a slight reduction in toxicity as indicated by changes in kidney weight and renal cortical slice accumulation of PAH and TEA. Pretreatment (oral) with 0 or 1.5 ml/kg acetone had no effect on cephaloridine toxicity (1000 mg/kg, i.p.). These findings suggested that attenuation of cephaloridine toxicity may be independent of the duration of diabetes. These results also indicated that glucose-mediated osmotic diuresis and acetone accumulation cannot account for reduced cephaloridine toxicity in diabetic rats.     

Nature of the toxicity of cyclosporin A in the rat

The potent immunosuppressive agent Cyclosporin A (CyA) causes a spectrum of toxicological effects in rats, of which the most striking is weight loss. Pair-feeding experiments have shown that this is caused, in part, by a short period of anorexia. However, even when the food intake has become normal the rats receiving CyA fail to gain weight. That CyA at the doses used causes increased protein catabolism is also indicated by a fall in serum albumin and a marked rise in blood urea unaccompanied by a corresponding rise in creatinine. CyA is mildly and reversibly hepatotoxic and there is slight nephrotoxicity in the rat on the basis of histology and small elevations in creatinine.     

氧化应激在糖尿病肾病中的意义及吡格列酮干预研究

目的观察糖尿病大鼠肾脏组织中氧化应激水平,探讨氧化应激在糖尿病肾病中的作用及吡格列酮干预效果。方法采用链脲佐菌素(STZ)诱导糖尿病模型。24只大鼠随机分为正常对照组(NC组)、糖尿病组(DM组)、吡格列酮干预组(3mg·kg-1.d-1,DT组),每组8只。12周末,测定各组相关生化指标。运用比色法检测肾皮质中丙二醛(MDA)的含量、铜锌超氧化物歧化酶(Cu-ZnSOD)及过氧化氢酶(CAT)的活性。结果与NC组相比,DM组和DT组血糖、胆固醇、甘油三酯、尿素氮、血肌酐、肾质量/体质量和尿蛋白定量(24h)值差异有统计学意义。DM组与NC组比较,肾皮质Cu-ZnSOD、CAT活性明显降低(P<0.01),MDA含量明显增加(P<0.01)。DT组与DM组比较,血糖、胆固醇、甘油三酯、尿素氮、血肌酐值差异无统计学意义(P>0.05),肾质量/体质量和尿蛋白定量(24h)明显降低(P<0.05);肾皮质CAT和Cu-ZnSOD活性增加(P<0.05),肾皮质MDA含量降低(P<0.05)。结论糖尿病大鼠肾脏组织中氧化应激水平升高,在糖尿病肾病发病机制中起重要作用。吡格列酮可能通过抗氧化作用改善糖尿病大鼠肾脏损害。     

Inhibition of gamma-glutamyl transpeptidase potentiates the nephrotoxicity of glutathione-conjugated chlorohydroquinones.

Administration of either 2,5-dichloro-3-(glutathion-S-yl)-1, 4-benzoquinone (DC-[GSyl]BQ) or 2,5,6-trichloro-3-(glutathion-S-yl)-1,4-benzoquinone (TC-[GSyl]BQ) to male Sprague-Dawley rats caused dose-dependent (50-200 mumol/kg; iv) renal proximal tubular necrosis, as evidenced by elevations in blood urea nitrogen (BUN), and in the urinary excretion of lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (gamma-GT) and glucose. Renal proximal tubular necrosis was also confirmed by histological examination of kidney slices prepared from DC-(GSyl)BQ- and TC-(GSyl)BQ-treated animals. Administration of the corresponding hydroquinone conjugates (DC-[GSyl]HQ and TC-[GSyl]HQ), prepared by reducing the quinones with a threefold molar excess of ascorbic acid, resulted in a substantial increase in nephrotoxicity. Moreover, in contrast to other glutathione (GSH)-conjugated hydroquinones, the nephrotoxicity of both DC-(GSyl)HQ and TC-(GSyl)HQ was potentiated when rats were pretreated with AT-125, an irreversible inhibitor of gamma-GT. Neither the quinone-GSH nor the hydroquinone-GSH conjugates caused any effect on liver histology or serum glutamate-pyruvate transaminase levels. The results suggest that coadministration of ascorbic acid with DC-(GSyl)BQ or TC-(GSyl)BQ decreases their interactions with extrarenal nucleophiles, including plasma proteins, and thus increases the concentration of the conjugates delivered to the kidney, and hence toxicity. Furthermore the ability of AT-125 to potentiate the nephrotoxicity of DC-(GSyl)HQ and TC-(GSyl)HQ suggests that metabolism of these conjugates by gamma-GT constitutes a detoxication reaction.     

Normalization of hyperglycaemia by oral vanadyl sulfate does not reverse diabetes-induced protection against cisplatin nephrotoxicity in streptozotocin-diabetic rats

Streptozotocin- and galactose-induced diabetic rats are protected against nephrotoxic effects of cisplatin. While the mechanism remains to be defined, protection is associated with a decrease in the accumulation of platinum in renal cortical tissues of streptozotocin-diabetic versus non-diabetic rats. A physiological abnormality common to streptozotocin and galactosemic models of diabetes is hyperglycaemia, suggesting that elevated sugars are involved in mediating protection of diabetic kidney against cisplatin nephrotoxicity. The current study focused on the effect of normalization of hyperglycaemia by vanadyl sulfate trihydrate on the initiation of protection and accumulation of platinum in kidneys of streptozotocin-diabetic rats. Streptozotocin-diabetic rats were treated with 0.75 mg/ml of vanadyl sulfate trihydrate in drinking water to normalize streptozotocin-induced hyperglycaemia. Vanadyl sulfate treatment normalized plasma glucose and glycosylated haemoglobin levels in streptozotocin-diabetic rats to values observed for non-diabetic rats. Intraperitoneal administration of cisplatin (5 mg/kg body weight) increased blood urea nitrogen by a factor >2.5 over baseline in both untreated and vanadyl-treated non-diabetic groups. Cisplatin-induced increases in blood urea nitrogen were 1.6 times baseline in both untreated and vanadyl-treated streptozotocin-diabetic rats. Renal platinum accumulation was significantly lower in streptozotocin-diabetic versus non-diabetic rats regardless of vanadyl sulfate treatment. Renal vanadium levels in all groups of diabetic rats were not significantly different from each other. These results indicate that normalization of plasma glucose levels with vanadyl sulfate in streptozotocin-diabetic rats did not reverse protection of streptozotocin-diabetic kidney against cisplatin nephrotoxicity.     

Difference between aortic and renal vascular reactivity in cyclosporin A treated rats and the effect of cicletanine

Summary 4 Groups of 2 month-old male Wistar rats were treated with a) cyclosporin A (CyA) 30 mg/kg/day alone, b) CyA plus cicletanine (Cic) 60 mg/kg/day, c) vehicle (vegetable oil) 1 ml/100 g rat/day and d) no treatment for 8 weeks. The reactivity of isolated papillary muscle to isoprenaline and Ca ²⁺ was not altered in any of the treated groups. Endothelium-dependent relaxation induced by acetylcholine was inhibited in aorta ring segments from CyA treated rats as compared to that of control and CyA+Cic-treated rats. The relaxation induced by acetylcholine in rat aortas was similar in all groups in the presence of 10 M indomethacin. Noradrenaline sensitivity of aortic segments was not affected by any treatments applied. The Ca²⁺-concentration response curves of aorta segments from CyA-treated and CyA+Cic-treated rats were shifted to the right as compared to control rats. In interlobar renal arteries the endothelium-dependent relaxation induced by acetylcholine was not affected by any form of treatment. In renal arteries 10 M indomethacin increased the maximal relaxation induced by acetylcholine about 50%. In these vessels noradrenaline sensitivity in CyA and CyA+Cic treated rats was higher than in controls. Cocaine, 3 M, shifted the noradrenaline concentration response curve to the left about 0.4 log units in all renal vessel groups, thus renal vascular smooth muscle sensitivity to noradrenaline was significantly greater in vessels from rats receiving CyA than in vessels from control rats. Administration of CyA induced only slight renal morphological changes. Cic was without effect on CyA induced morphological abnormalities. The results indicate that Cic is able to reverse the inhibitory effect of CyA on endothelium-dependent relaxations in aorta but does not affect the increased noradrenaline sensitivity of renal arteries associated with CyA treatment and was without effect on CyA induced changes in renal morphology. Treatment with CyA alone or in combination with Cic had no effect on the contractile force of the papillary muscle, indicating that CyA only affects function of vascular but not cardiac tissue. Send offprint requests to E. Mikkelsen at the above address     

Effect of edaravone in diabetes mellitus-induced nephropathy in rats

Edaravone, a synthetic-free radical scavenger, has been reported to reduce ischemia-reperfusion-induced renal injury by improving tubular cell function, and lowering serum creatinine and renal vascular resistance. The present study investigated the effect of edaravone in diabetes mellitus-induced nephropathy in rats. A single administration of streptozotocin (STZ, 55 mg/kg, i.p.) was employed to induce diabetes mellitus in rats. The STZ-administered diabetic rats were allowed for 10 weeks to develop nephropathy. Mean body weight, lipid alteration, renal functional and histopathology were analysed. Diabetic rats developed nephropathy as evidenced by a significant increase in serum creatinine and urea, and marked renal histopathological abnormalities like glomerulosclerosis and tubular cell degeneration. The kidney weight to body weight ratio was increased. Moreover, diabetic rats showed lipid alteration as evidenced by a signifi cant increase in serum triglycerides and decrease in serum high-density lipoproteins. Edaravone (10 mg/kg, i.p., last 4-weeks) treatment markedly prevented the development of nephropathy in diabetic rats by reducing serum creatinine and urea and preventing renal structural abnormalities. In addition, its treatment, without significantly altering the elevated glucose level in diabetic rats, prevented diabetes mellitus-induced lipid alteration by reducing serum triglycerides and increasing serum high-density lipoproteins. Interestingly, the renoprotective effect of edaravone was comparable to that of lisinopril (5 mg/kg, p.o, 4 weeks, standard drug). Edaravone prevented renal structural and functional abnormalities and lipid alteration associated with experimental diabetes mellitus. Edaravone has a potential to prevent nephropathy without showing an anti-diabetic action, implicating its direct renoprotection in diabetic rats.     

Effects of rinbacin extract on rat kidney

The aqueous leaf extract of rinbacin was tested for toxic effects on prepubertal rat kidneys following chronic administration. Two doses of rinbacin extract (26.25 g/l and 52.50 g/l) were administered in the rats' drinking water for 13 weeks, and various toxicologic indices tested. Histological study of the kidneys was also carried out at the expiration of the test period. Rinbacin at both dose sizes significantly (p<0.05) increased the absolute and relative kidney weights. Also the serum HCO3- level was significantly (p<0.05) increased, while the serum K+ level was decreased significantly at both dose levels. Only the high dose significantly (p<0.05) increased the serum urea level of the rats. Histological study showed that rinbacin at both dose sizes caused renal pathologic changes, which included necrosis and cellular infiltration of glomeruli and epithelia of the tubules. The effects were less marked in the low dose than the high dose group. Chronic administration of rinbacin extract induces nephrotoxicity in young rats.