Pharmacokinetic changes of intravenous tacrolimus in rats with uranyl nitrate-induced acute renal failure

Because the physiological changes that occur in patients with acute renal failure could alter the pharmacokinetics of the drugs, the pharmacokinetics of tacrolimus were investigated after 1-min intravenous administration of the drug (1 mg kg(-1)) to control rats and rats with uranyl nitrate-induced acute renal failure (rats with U-ARF). The impaired kidney and hepatic functions were observed in rats with U-ARF on the basis of physiological parameters and by microscopy of the tissues. After intravenous infusion of tacrolimus, the total area under the blood concentration-time curve from time zero to time infinity was significantly greater in rats with U-ARF than that in control rats (35.8 versus 29.2 microg min mL(-1)) due to significantly slower total body clearance of tacrolimus (27.9 versus 34.3 mL min(-1) kg(-1)), and this could be due to significantly slower nonrenal clearance (because of impaired hepatic function). The urinary excretion of unchanged tacrolimus was almost negligible for both groups of rats, therefore, effects of kidney impairment on the pharmacokinetics of tacrolimus seemed to be minor.     

Effects of dexamethasone on the pharmacokinetics of adriamycin after intravenous administration to rats

Adriamycin was metabolized to adriamycinol by the cytoplasmic aldo-keto reductase and adriamycin and adriamycinol were further metabolized to their deglycosylated aglycones, M3 and M4, respectively, by cytochrome P450. SKF-525A (a cytochrome P450 inhibitor) and dexamethasone (a cytochrome P450 inducer) were pretreated to rats. Adriamycin, 16 mg/kg, was infused over 1-min via the jugular vein of each rat. After pretreatment with SKF-525A, the area under the plasma concentration-time curve of adriamycin from time zero to the last measured time in plasma, 8 h (537 versus 155 microg x min/ml) was significantly greater, and the 24-h urinary excretion of M3 (1.65 versus 23.8 microg), and M3, M4, and their glucuronide and/or sulfate conjugates (33.7 versus 3.38 microg) were significantly smaller than those in control rats suggesting that the formation of M3 and M4 were inhibited by SKF-525A. After pretreatment with dexamethasone, the 24-h urinary excretion of M3 (94.5 versus 23.8 microg), M4 (8.43 versus 2.78 microg), and M3, M4, and their glucuronide and/or sulfate conjugates (116 versus 33.7 microg) were significantly greater than those in control rats, suggesting that the formation of M3 and M4 seemed to be induced by dexamethasone.     

Pharmacokinetics of tolbutamide after oral administration in rabbits with folate-induced renal failure

The pharmacokinetic changes of tolbutamide were studied after oral administration to normal rabbits and mild and medium folate-induced renal failure rabbits. Tolbutmide 50 mg/kg was orally administered to the rabbits. The plasma concentrations of tolbutamide were significantly increased (p<0.05) at 9 to 24 hr in mild and medium folate-induced renal failure rabbits compared with those in normal rabbits. Therefore, the area under the plasma concentration-time curves (AUC) was significantly higher (p<0.05 and p<0.01 respectively) in mild and medium folate-induced renal failure rabbits (2906 microg/ml x hr and 4074 microg/ml x hr) than that in normal rabbits (2295 microg/ml x hr). The cumulative urinary excretion of tolbutamide was significantly decreased (p<0.05) in medium folate-induced renal failure rabbits (3.3 mg) compared with the normal rabbits (5.9 mg). The elimination rate constant (Kel) of tolbutamide was significantly slower in medium folate-induced renal failure rabbits (0.027 hr(-1)) than that in normal rabbits(0.044 hr(-1)). The terminal half-life of tolbutamide in medium folate-induced renal failure rabbits (25.5 hr) was significantly longer (p<0.01) than in normal rabbits (15.7 hr). These results could be considered as possibly due to inhibited excretion of tolbutamide metabolites or retarded metabolism of tolbutamide.     

Possible involvement of myofibroblasts in cellular recovery of uranyl acetate-induced acute renal failure in rats

Cellular recovery in acute renal failure is a form of wound healing. Fibroblast-like cells or myofibroblasts are involved in wound healing. We examined the serial changes in tubular damage and origin and kinetics of regenerating cells in uranyl acetate-induced acute renal failure, with a special emphasis on interstitial myofibroblasts. Acute renal failure was induced in rats by intravenous injection of uranyl acetate (5 mg/kg). All rats received bromodeoxyuridine intraperitoneally 1 hour before sacrifice. Serial changes in the distribution of tubular necrosis and bromodeoxyuridine-incorporated or vimentin-positive regenerating cells, and their spatial and temporal relation to alpha-smooth muscle actin-positive myofibroblasts as well as ED 1-positive monocytes/macrophages were examined. Necrotic tubules initially appeared around the corticomedullary junction after uranyl acetate injection, then spread both downstream and upstream of proximal tubules. Peritubular alpha-smooth muscle actin-positive myofibroblasts appeared and extended along the denuded tubular basement membrane, establishing network formation throughout the cortex and the outer stripe of outer medulla at days 4 to 5. Tubular regeneration originated in nonlethally injured cells in the distal end of S3 segments, which was confirmed by lectin and immunohistochemical staining using markers for tubular segment. Subsequently, upstream proliferation was noted along the tubular basement membrane firmly attached by myofibroblasts. During cellular recovery, no entry of myofibroblasts into the tubular lumen across the tubular basement membrane was noted and only a few myofibroblasts showed bromodeoxyuridine positivity. The fractional area of alpha-smooth muscle actin-positive interstitium reached a peak level at day 7 in the cortex and outer stripe of outer medulla, then gradually disappeared by day 15 and remained only around dilated tubules and in the expanded interstitium at day 21. ED 1-positive monocytes/macrophages were transiently infiltrated mainly into the region of injury. They did not show specific association with initially necrotic tubules, but some of them located in close proximity to regenerating tubules. Nonlethally injured cells at the distal end of proximal tubules are likely to be the main source of tubular regeneration, and the transient appearance of interstitial myofibroblasts attached to the tubular basement membrane immediately after tubular necrosis might play a role in promoting cellular recovery in possible association with monocytes/macrophages in uranyl acetate-induced acute renal failure.     

Pharmacokinetic changes of intravenous 2-(allylthio) pyrazine, a chemoprotective agent, in rats with acute renal failure induced by uranyl nitrate

It was reported that the total body clearance (CL) of 2-(allylthio)pyrazine (2-AP) was significantly faster after intravenous administration of 2-AP to rats pretreated with 3-methylcholanthrene (an inducer of CYP1A1/2 and 2E1 in rats) than that in control rats. It was also found that the CYP2E1 increased 2-4 times in rats with acute renal failure induced by uranyl nitrate (U-ARF) compared with those in control rats. Therefore, it could be expected that the pharmacokinetics of 2-AP could be changed in rats with U-ARF. After intravenous administration of 2-AP, 50 mg/kg, to rats with U-ARF, the area under the plasma concentration-time curve from time zero to time infinity (AUC) of 2-AP was significantly smaller (1030 versus 1360 microg min/ml) and this could be due to significantly faster CL of 2-AP (48.4 versus 36.8 ml/min/kg). This could be due to increased CYP2E1 in rats with U-ARF. More studies are required to find increased metabolite(s) of 2-AP in rats with U-ARF.     

Important role for fibronectin-EIIIA during renal tubular repair and cellular recovery in uranyl acetate-induced acute renal failure of rats

The present study was designed to identify the source and kinetics of an alternatively spliced "embryonic" cellular fibronectin EIIIA (cFn-EIIIA) in relation to regenerating renal tubules in uranyl acetate (UA)-induced acute renal failure (ARF) in rats. Damage of the proximal tubules was found as early as day 2 after induction of ARF, peaked at day 5, and was almost substituted by epithelial relining by day 7. Immunohistochemistry showed de novo deposition of cFn-EIIIA in peritubular regions as early as day 2, then on the tubular basement membrane (TBM) after day 4. 1 Integrin, the receptor for Fn, was mainly found at the basal side of tubules in the normal control and increased in the interstitium after induction of ARF, but the staining pattern gradually returned to the control after day 7. Immunoelectron microscopy revealed that cFn-EIIIA was produced initially by the peritubular endothelium and later by fibroblastic cells and was deposited to the TBM, on which regenerating tubules proliferated, probably with cFn-EIIIA production. 1 Integrin was expressed in cFn-EIIIA-producing cells, especially in regenerating tubular cells, suggesting that cFn-EIIIA signal transduction affects regenerating tubules. Transforming growth factor (TGF)-1 was found in some damaged proximal tubules and interstitial cells after induction of ARF and later in the regenerating tubules. CFn-EIIIA and 1 integrin mRNA levels were upregulated as early as day 2. TGF-1 mRNA level significantly increased after day 3, suggesting a modulatory role for TGF-1 on cFn-EIIIA production, but not by day 2. Our data suggest that cFn-EIIIA production by the endothelium during the very early response to tubular injury and by fibroblastic cells and regenerating tubules may play an important role in the cellular recovery of UA-induced ARF in rats.     

Transient myofibroblast differentiation of interstitial fibroblastic cells relevant to tubular dilatation in uranyl acetate-induced acute renal failure in rats

To investigate the mechanisms of myofibroblast differentiation of interstitial fibroblastic cells (FCs) in rats with uranyl acetate-induced acute renal failure (ARF), we examined the relationship between the expression of -smooth muscle actin (-SMA), myofibroblast phenotype and tubular dilatation as well as cell shape and adhesion of FCs. Peritubular -SMA-positive myofibroblasts appeared after induction of ARF and extended along the damaged, dilated proximal tubules and then almost disappeared after proximal tubular recovery. The perimeter of proximal tubules correlated with fractional areas stained for -SMA (P<0.001). Most -SMA-positive cells did not incorporate [³H]-thymidine, indicating a low proliferative activity. Transmission electron microscopy showed that FCs increasingly attached to the tubular basement membrane by elongated cytoplasm-containing microfilament bundles, which formed abundant adherens and gap junctions from day 4 to day 7. Scanning electron microscopy showed hypertrophic FCs covering large areas of tubules after induction of ARF. Administration of chlorpromazine, which can inhibit cytoskeletal movement, after induction of ARF partially inhibited myofibroblast differentiation of FCs immunohistochemically and morphologically and resulted in more dilated proximal tubules in concert with aggravation of renal dysfunction and inhibition of regenerative repair at day 4 than vehicle-administered rats. Our results indicate that mechanical tension, judged by tubular dilatation, may contribute to the induction of -SMA phenotype with increased stress fiber formation and intercellular junctions in FCs to support damaged nephron structures by adjusting tensional homeostasis in rats with uranyl acetate-induced ARF.     

Effects of neostigmine on the pharmacokinetics of intravenous parathion in rats

It was reported that the area under the plasma concentration-time curve from time zero to time infinity (AUC) of parathion was significantly smaller and the time-averaged total body clearance (CL) of parathion was significantly faster after intravenous administration of parathion to rats pretreated with dexamethasone than those in control rats. This was supported by significantly faster intrinsic clearance of parathion to form paraoxon in hepatic microsomal fraction of rats pretreated with dexamethasone. The above data suggested that parathion was metabolized to paraoxon by dexamethasone-inducible hepatic cytochrome P450 (CYP) 3A in rats. The purpose of this study is to explain the protective effects of neostigmine against paraoxon toxicity by suppressing CYP3A and hence decreasing formation of toxic metabolite, paraoxon by neostigmine. The pharmacokinetic changes of parathion and its active metabolite, paraoxon, were investigated after intravenous administration of parathion, 3 mg/kg, to control Sprague-Dawley rats and the rats pretreated with neostigmine (200 microg/kg, intraperitoneal injection 30 min before parathion administration). After 1-min intravenous infusion of parathion to rats pretreated with neostigmine, the AUC of parathion (65.1 versus 74.3 microg min/ml) was significantly greater and the CL of parathion (45.1 versus 40.4 ml/min/kg) was significantly slower than those in control rats. Based on in vitro hepatic microsomal studies, neostigmine inhibited significantly the erythromycin N-demethylase activity (1.03 versus 0.871 nmol/mg protein/min), mainly mediated by hepatic cytochrome P450 3A in rats. The above data suggested that the formation of paraoxon was inhibited in rats pretreated with neostigmine by inhibiting CYP3A.     

Effects of aging on expression of ischemic acute renal failure in rats

Ischemic acute renal failure is principally a disease of the elderly, but the effect of aging on renal susceptibility to ischemic damage has not been defined. To address this issue, adolescent (3-4 months), mature (12-13 months), and aged (24-25 months) rats underwent base-line renal functional assessments, and then they were subjected to a standardized ischemic event (37-minute, bilateral renal artery occlusion). The loss of renal function [assessed by azotemia and creatinine clearance, (Ccr)] and the severity of tubular damage (necrosis, casts) were determined 24 hours later. Base-line functional assessments indicated no significant differences in Ccr/100 gm body weight between the groups, but urinary protein excretion increased with age (p less than 0.001). In response to renal artery occlusion, the adolescent, mature, and aged rats lost 59 +/- 4, 82 +/- 4, and 94 +/- 1% of their base-line Ccr (p less than 0.01), respectively. Among the proteinuric rats, no correlation was noted between percent loss Ccr and urinary protein excretion. Despite the large differences in postischemic renal function, the extent of tubular morphologic damage did not differ among the groups. The percent loss Ccr did not correlate with necrosis (r = -0.02) or casts (r = 0.07). Although focal glomerulosclerosis and mild tubular atrophy were noted in the aged kidneys these lesions were minimal to absent in the mature rats. We conclude that aging increases susceptibility to severe ischemic acute renal failure in the rat, an effect that is apparent even during a transition from the adolescent to the mature state. This finding cannot be simply ascribed to increasing proteinuria, a loss of renal functional reserve, or to increased tubular morphologic damage. The data are most consistent with the view that underlying age-related glomerular/hemodynamic changes lead to an exaggerated functional decline in response to ischemic renal injury.     

Effects of combined oral administration and intravenous injection on maintaining decreased systemic tyrosine levels in rats

Our previous studies have indicated that encapsulated tyrosinase and crosslinked hemoglobin with tyrosinase (polyhemoglobin-tyrosinase) decrease systemic tyrosine level significantly in rats. However, we need a few days of oral administration of encapsulated tyrosinase before the systemic tyrosine level starts to decrease. Although intravenous injection of polyhemoglobin tyrosinase can lower the systemic tyrosine to about 10% within an hour, the level increases towards normal after 24 h. We therefore investigate the effects of intravenous injection of polyhemoglobin-tyrosinase combined with oral administration of encapsulated tyrosinase on lowering the systemic tyrosine level. In addition, we further optimize this combined method for lowering systemic tyrosine in animal studies and have found out that two intravenous injections of polyhemoglobin-tyrosinase followed by three times a day oral administration of encapsulated tyrosinase could immediately lower the body tyrosine and maintain this low level as long as the oral administration is continued.     

Temporary changes in macrophages and MHC class-II molecule-expressing cells in the tubulointerstitium in response to uranyl acetate-induced acute renal failure in rats

The present study was designed to asses the dynamic changes in macrophages (Møs) with or without expression of major histocompatibility complex (MHC) class-II molecule in response to uranyl acetate-induced acute renal failure (ARF) in rats. ED1+ monocytes/Møs infiltrated into the interstitium as early as day 2, peaked in number on day 5 after uranyl acetate-induced ARF. ED1+ cells did not correlate with necrotic tubules but accumulated abundantly in the vicinity of the Ki67+ regenerating proximal tubules around days 4–5. Afterward, regeneration of proximal tubules was accelerated. After day 5, some ED1+ cells entered the tubular lumen, and became ED1+ giant cells, which had features of phagocytic Møs by immunoelectron microscopy, peaking in number on day 7. Most ED1+ cells did not incorporate [³H]-thymidine, indicating lack of active proliferation. The number of OX6+ cells (directed to MHC class-II molecule) in the interstitium significantly increased on day 4 and peaked on day 5. Double staining revealed that ED1+OX6– cells entered the tubular lumen while ED1+OX6+ cells remained in the peritubular regions. Osteopontin (OPN) protein and mRNA were significantly upregulated. No specific relationship could be found between OPN+ regenerating proximal tubules and ED1+ cells, but most ED1+ giant cells were OPN+ and intermingled among OPN+ cell debris. Our findings suggest that ED1+ Møs are actively associated with regenerating proximal tubules and, thus, might promote proximal tubular regeneration. ED1+OX6– Møs may function as scavengers and phagocytose cellular debris in the tubular lumen, cleaning the wound site. OPN might be involved in this process. ED1+OX6+ Møs in the peritubular regions may act as outpost of the defense system to monitor incoming antigens. Our data indicate that Møs with or without expressing MHC class-II molecule contribute to the defense and repair of injured proximal tubules in this ARF.     

硝苯吡啶对大鼠急性肾衰时肾功能及内源性内皮素释放的影响

目的和方法：在甘油致大鼠急性肾功能衰竭（ＡＲＦ）模型上，观察了硝苯吡啶对ＡＲＦ大鼠肾功能及内源性内皮素（ＥＴ）释放的影响。结果：ＡＲＦ大鼠肾皮质钙含量及血浆ＥＴ（ＰＥＴ）水平明显升高，肾功能严重受损，肾小管ＥＴ免疫反应阳性颗粒显著增多；而硝苯吡啶则使ＡＲＦ大鼠肾皮质钙含量及ＰＥＴ水平明显降低，肾小管ＥＴ免疫反应阳性颗粒明显减少，肾功能得到改善。结论：硝苯吡啶改善肾功能的作用可能与其抑制ＥＴ的合成与释放以及拮抗ＥＴ的生物学作用有关。     

Effects of cysteine on the pharmacokinetics of intravenous adriamycin in rats with protein-calorie malnutrition

In rats with protein-calorie malnutrition (PCM, 5% caseine diet for 4 weeks), hepatic cytochrome P450 levels suppressed markedly and cytochrome P450 mRNAs decreased significantly compared with those in control rats (23% caseine diet for 4 weeks), however, the values completely (or partially) returned to control levels by a week (from fourth week) of cysteine supplementation (rats with PCMC) (Cho, Kim et al., Arch. Biochem. Biophys. 1999, 372: 150-158). The formation of aglycone metabolites of adriamycin and adriamycinol, M3 and M4, respectively, seemed to be induced (Lee and Lee, Res. Commun. Mol. Pathol. Pharmacol. 1999, 105: 87-96) by pretreatment with dexamethasone (possibly by hepatic cytochrome P450 RL 33/cDEX, Komori and Oda, J. Biochem. 1994, 116: 114-120) in rats. Adriamycin, 16 mg/kg, was administered intravenously in 1-min to control rats and rats with PCM and PCMC. In rats with PCM, the plasma concentrations of adriamycin was higher (the area under the plasma concentration-time curve from time zero to 12 hr, AUC(0-12 hr), tended to be higher) and 24-hr urinary excretion of M3 (including its 'conjugates') seemed to increase than those in control rats, suggested that the formation of M3 was inhibited in rats with PCM. In rats with PCMC, the plasma concentrations of adriamycin were lower (the AUC(0-12 hr) was significantly smaller) and 24-hr urinary excretion of M3 (including its 'conjugates') were significantly greater than those in rats with PCM, suggested that the formation of M3 increased significantly by cysteine supplementation by restoring the enzyme system(s) that metabolize adriamycin to M3. The altered pharmacokinetic parameters of adriamycin mentioned above in rats with PCM returned to greater than those of control rats after cysteine supplementation (rats with PCMC). Above data suggested that other hepatic cytochrome P450 isozyme(s) which catalyze(s) the formation of M3 from adriamycin could be induced by cysteine supplementation.     

Effects of acute cisplatin administration on renal ATPase activities and magnesium excretion of rats

Male Wistar rats were killed 1, 2, or 4 days after a single intraperitoneal injection of cisplatin (5 mg/kg). Functional renal indices, enzymatic activities, and morphological variables were studied. One day after the injection, the treated group showed an increase in the magnesium and phosphate fractional urinary excretion (FE) vs the control group (FE Mg = 5.2 +/- SEM 0.5% vs 13.0 +/- 1.7%; P less than 0.01; and FE P = 4.7 +/- 0.7% vs 14.0 +/- 1.9%; P less than 0.01). Two days after cisplatin administration, a decrease in creatinine clearance of treated animals was found, to 0.33 +/- 0.03 vs 0.51 +/- 0.03 ml/min; P less than 0.05. Na-K-ATPase and ouabain-insensitive ATPase activities were studied in the proximal convoluted tubule, the medullary thick ascending limb of the Henle's loop (mTAL), and the distal convoluted tubule. Only in mTAL one day after the cisplatin injection was there a decrease in Na-K-ATPase activity in the treated group vs controls (1103 +/- 145 vs 1734 +/- 189 pmol Pi/mm.h; P less than 0.05). Morphological studies showed a decrease in mTAL diameters on day 1, and an increase in proximal convoluted tuble diameters at day 2 of treated rats vs controls, at 27.8 +/- 0.6 vs 31.4 +/- 0.7 microns; P less than 0.05, and 50.4 +/- 1.2 vs 47.4 +/- 0.2 microns; P less than 0.05 respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of subcutaneous versus intravenous administration of cyclosporin A on rat thymic histology and pharmacokinetics.

Cyclosporin A (CsA) was administered to rats by repeated subcutaneous (s.c.) or intravenous (i.v.) injections for 14 days. Changes in thymic histology were independent of the route of administration. Blood concentration--time profiles of CsA were similar at dose levels of i.v. 7.5 and s.c. 15 mg/kg/day, respectively. So, provided that the dose is reduced, i.v. injection can serve as an adequate alternative to s.c. injection, thereby preventing unwanted painful side-effects associated with the latter route of administration.     

Effects of a therapy with losartan and quinaprilat on the progression of chronic renal failure in rats after a single dose of uranyl nitrate or 5/6 nephrectomy

The renoprotective effect of losartan and quinaprilat was tested in two different animal models of renal failure [female Wistar rats, single administration of 0.5 mg uranyl nitrate (UN)/100 g body wt. or 5/6 nephrectomy (5/6NX)]. Losartan (1 mg/100 g body weight [wt.]) and quinaprilat (1mg/100 g body wt.) were administered intraperitoneally, once daily, starting 10 days after UN and one week after 5/6NX till the end of 10 weeks experimental period. Parameters characterizing the therapeutic effect were blood pressure, urinary protein excretion 4 and 10 weeks after the injury, and p-aminohippurate accumulation in renal cortical slices in vitro, hydroxy-proline concentration in renal tissue and morphology at the end of the experiment.

Summarizing our results we state: (1) the angiotensin 1 receptor blocker losartan is more effective in UN-treated than in 5/6 NX rats, and (2) the angiotensin converting enzyme inhibitor quinaprilat is more effective than losartan because of the amelioration of blood pressure and OH-proline concentration in renal tissue of UN-treated rats.     

Experimental intravenous cell therapy of acute and chronic renal failure

The therapeutic effect of intravenous injection of human fetal bone marrow mesenchymal stem cells or summary culture of kidney cells were studied on models of chronic or acute renal failure in outbred albino rats. Both cell types promoted improvement and normalization of the renal function in rats with stable chronic renal insufficiency (2 weeks after kidney cell injection, 1 month after bone marrow mesenchymal stem cell injection). Renal function remained normal or subnormal during the delayed period (3–3.5 months after injection). In rats with latent stage of chronic renal insufficiency, exacerbation was induced by additional 40-min ischemia. All rats receiving intravenous injection of saline died. Improvement of the functional parameters started 2 weeks after injection of kidney cells or bone marrow mesenchymal stem cells, and normalization was observed after 1.1–5 months. During the delayed period (after 3–4 months), functional parameters retained at normal or subnormal levels. In experimental series III, all rats with acute renal failure intravenously injected with saline (control) died from uremia on days 2–4. After injection of kidney cells 50% rats survived and renal function in these animals returned to normal after 2 weeks. After injection of bone marrow mesenchymal stem cells 83% rats survived, functional parameters returned to normal after 3 weeks. __________ Translated from Kletochnye Tehnologii v Biologii i Medicine, No. 1, pp. 52–57, January, 2007     

Effects of chronic oral nickel chloride administration on glycaemia and renal function in normal and diabetic rats

Effects of nickel on glycaemia are conflicting. We have investigated the effects of oral administration of nickel chloride for 5 weeks on glycaemia and renal function in normal and streptozotocin-diabetic rats. The results show increase (P< 0.05) in plasma glucose and sodium and decrease (P< 0.05) in insulin concentrations only in normal experiment by comparison with normal control. Plasma potassium concentration was elevated (P< 0.05) only in diabetic experiment by comparison with diabetic control. Plasma urea levels were raised (P< 0.05) in both groups of experiments by comparison with respective controls and plasma creatinine level was elevated (P< 0.05) only in diabetic experiment. GFR was reduced (P< 0.05) only in normal experiment by comparison with control. Kidney weights in normal and diabetics were not effected by nickel chloride administration. Total food and water intakes in normal and diabetic experiments were lower by comparison with respective controls. These were accompanied by failure to increase body weights. In addition, total urine volume and sodium were reduced in normal and diabetic experiments. Urine potassium was lower only in normal experiment by comparison with normal control. We conclude that chronic nickel chloride administration induces hyperglycemia possibly through reduction in blood insulin levels and could be toxic to renal function.