The effect of methylprednisolone on cisplatin-induced nephrotoxicity in rat renal cortical slices

To investigate the protective action of methylprednisolone against cisplatin nephrotoxicity, the effect of in vivo pretreatment with methylprednisolone on the cisplatin-induced reduction inp-aminohippurate (PAH) accumulation and gluconeogenesis was examined using renal cortical slices prepared from Sprague-Dawley rats. The PAH accumulation in the kidney slices prepared from methylprednisolone-pretreated rats was significantly reduced following in vitro incubation with 2 mM cisplatin, to a degree equal to that observed in the slices prepared from untreated rats. However, the inhibitory effect of cisplatin on gluconeogenesis in the renal cortical slices obtained from methylpredimisolone-pretreated rats was significantly smaller than that seen in the slices from untreated rats. Our present studies suggest that in vivo pretreatment with methylprednisolone may contribute to its protective effect against cisplatin nephrotoxicity through the process of gluconeogenesis in renal epithelial cells.     

Protective effect of piperacillin against the nephrotoxicity of cisplatin in rats.

The protective effect of piperacillin against the nephrotoxicity of cisplatin was compared with that of fosfomycin in Fischer 344 rats. Blood urea nitrogen, serum creatinine, and morphological changes were evaluated as the renal toxicological parameters. Rats receiving 2 mg of cisplatin per kg of body weight for 5 days showed significant (P less than 0.01 by multiple-comparison test) elevation of blood urea nitrogen and serum creatinine concentrations compared with rats receiving saline alone and also exhibited development of cell lesions in the pars recta of the tubules in the outer stripe of the outer medulla. However, piperacillin (250 and 1,000 mg/kg) significantly (P less than 0.01 by multiple-comparison test) reduced these toxicological parameters in comparison with results for cisplatin alone. The protective effect of piperacillin was superior to that of fosfomycin, although platinum levels in the kidney were higher with the combination of cisplatin and piperacillin than with cisplatin plus fosfomycin. Although the nephrotoxicity of cisplatin was also reduced when cisplatin was administered concomitantly with sodium chloride in mole-equivalents to 250 and 1,000 mg of piperacillin per kg, its protective effect was less than that of the corresponding piperacillin dose. These results suggest that piperacillin may have a role as a protective agent against the nephrotoxicity of cisplatin.     

Reduction of cisplatin nephrotoxicity by procainamide: does the formation of a cisplatin-procainamide complex play a role?

Procainamide protects mice bearing P388 leukemic cells against the toxicity of cisplatin without diminishing antitumor activity. The mechanism of action of procainamide protection was investigated both in vitro and in vivo. HPLC studies showed that procainamide forms a complex with cisplatin in vitro that has a UV spectrum similar to that of DPR, a triamine platinum complex that contains procaine as ligand. We report here the effect of the reaction product of cisplatin and procainamide on both cisplatin-induced DNA interstrand cross-links (ISCLs) and on the total DNA platination of isolated DNA. Total DNA platination in vitro of isolated DNA was increased by 113% (P <.01) and 17% (P <.05) after incubation times of 1.75 and 6 h, respectively, compared with products from the reaction of cisplatin with water. Furthermore, the reaction product of cisplatin and procainamide was bound to DNA to a significantly greater extent than was cisplatin itself. ISCLs were decreased by 41% when this drug combination was incubated with DNA for 1.75 h, but no changes were observed after incubation for 6 h. We also examined the influence of the time interval between administration of cisplatin and procainamide on normal kidney injury, the renal distribution and urinary excretion of platinum, and the formation of cisplatin-DNA adducts in renal tissue of Sprague-Dawley rats after i.p. administration of 7.5 mg/kg cisplatin either with or without procainamide. The plasma concentrations of urea and creatinine and kidney histology demonstrated that procainamide provided effective protection in vivo in the rat when administered either simultaneously or at 0.5 and 1 h before or after cisplatin. The protection was accompanied by both higher renal levels of platinum and cisplatin-DNA adducts and by an increase in the formation of ISCLs. Moreover, a dose-dependent reduction of urinary excretion and concentration of platinum was also observed. We propose that procainamide, after accumulation in the kidney, may coordinate with cisplatin to form a less toxic DPR-like complex that renders rats less susceptible to cisplatin-induced toxicity.     

Long-term effects of acetazolamide and sodium chloride loading on cisplatin nephrotoxicity in the rat

The protective effect of acetazolamide or sodium chloride loading on cisplatin nephrotoxicity was investigated in rats. After a single dose of cisplatin (5 mg kg-1 i.p.) kidney function was studied after 5, 28 and 84 days. Acetazolamide (75 mg kg-1 i.p.) was administered as a single dose prior (30 min) to the cisplatin injection. By the time of cisplatin administration, the rats were sodium depleted except the sodium-loaded group. Five days after the cisplatin administration all rats received a regular rat chow for the rest of the experiment. Cisplatin alone caused renal failure that could be observed for up to 12 weeks (ClCr 0.32 +/- 0.13 vs. 0.62 +/- 0.06 ml min-1 x 100 g BW-1) with polyuria (UVol 41.2 +/- 4.5 vs. 18.4 +/- 4.6 ml 24 h-1). Pretreatment with acetazolamide was the most protective manoeuvre tested. Five days after cisplatin, kidney function was significantly better than in rats treated with cisplatin alone (ClCr 0.21 +/- 0.06 vs. 0.03 +/- 0.01 ml min-1 x 100 g BW-1), after 28 days the only sign of nephrotoxicity was polyuria (UVol 28.9 +/- 3.7 vs. 19.0 +/- 2.6 ml 24 h-1) after 84 days no differences could be observed at all. Sodium chloride loading was less protective on cisplatin nephrotoxicity. Impaired renal function could still be observed after 12 weeks (ClCr 0.41 +/- 0.05 vs. 0.62 +/- 0.06 ml min-1 x 100 g BW-1) with no difference in comparison with the rats treated with cisplatin alone. However, since 12 rats died in the group having received cisplatin alone and only one rat in the high-salt group, sodium chloride loading is regarded as being advantageous over sodium depletion on cisplatin nephrotoxicity.     

Plasma and urinary endothelin-1 in focal segmental glomerulosclerosis

The kidney is an important site of endothelin-1 (ET-1) production and is particularly susceptible to ET-1 action. Infusion of ET-1 in rats induces both functional and morphological alterations in the kidneys. Increased plasma level of ET-1 has been reported in patients with chronic renal failure. However, there are still no reports on the plasma and urinary ET-1 levels in patients with focal segmental glomerulosclerosis (FSGS). In the present study, we have measured the plasma concentration and urinary excretion rate of ET-1 in 15 patients with nephrotic syndrome due to FSGS, and observed the serial changes of plasma and urinary ET-1 in nephrotic rats with FSGS, induced by repeated injection with puromycin aminonucleoside (PAN). ET-1 was measured with radioimmunoassay. The results showed that plasma ET-1 concentration in FSGS patients was significantly higher than in normal controls (P < 0.05), and that urinary ET-1 excretion rate was also significantly higher in FSGS patients than in normal controls (P < 0.01). In FSGS patients, the plasma and urinary ET-1 was significantly correlated (P < 0.05), and the urinary ET-1 excretion rate was significantly correlated with the amount of proteinuria (P < 0.05) and the glomerular sclerosing score (P < 0.01). In the ten rats with PAN-induced FSGS, serial examination showed a significant increase in plasma ET-1 after 8 weeks of injections, while the urinary ET-1 excretion rate showed a biphasic increase that showed a peak after 4 to 6 weeks. The same changes in plasma and urinary ET-1 levels were not observed in control rats injected with normal saline at the same frequency. Our results suggest that ET-1 may be involved in the pathogenesis of FSGS in both humans and rats.     

Association between increased atrial natriuretic peptide and reduced cisplatin nephrotoxicity in rats.

Plasma atrial natriuretic peptide (ANP) concentrations were monitored in two experimental models of protection from cisplatin nephrotoxicity. Sprague-Dawley rats made diabetic with streptozotocin (65 mg/kg) were protected from cisplatin-induced nephrotoxicity when compared to control rats as indicated by reduced plasma creatinine (0.49 +/- 0.02 vs. 0.9 +/- 0.06 mg/dl; P less than .001) and blood urea nitrogen concentrations (18.51 +/- 1.4 vs. 43.08 +/- 2.1 mg/dl; P less than .001). Plasma ANP was also increased with experimental diabetes (76.5 +/- 8.98 fmol/ml) vs. normoglycemic controls (43.8 +/- 8.9 fmol/ml; P less than .02). When diabetic rats were treated with insulin, the renal protection observed with the diabetic state was reversed (creatinine, 0.70 +/- .05 mg/dl); plasma ANP concentrations were also reduced (52.2 +/- 15.2 fmol/ml). Renal platinum concentrations were significantly lower in the diabetic group and the reversal of diabetic-induced renal protection with insulin was associated with increased renal platinum concentrations. In rats given a single i.p. dose of cisplatin (5 mg/kg), a reduction in cisplatin-induced nephrotoxicity was observed when 5% NaCl was the vehicle of choice compared to that seen in rats given the same dose of drug in 0.9% saline (creatinine, 0.43 +/- 0.07 with 5% NaCl vs. 0.63 +/- 0.03 with 0.09% NaCl). NaCl (5%) administration also resulted in increased plasma ANP concentrations when compared to rats receiving equivalent volumes of 0.9% NaCl (88.4 +/- 6.2 vs. 50.5 +/- 5.6 fmol/ml, respectively). These data suggest that increased endogenous ANP may be a mechanism of renal protection common to both experimental diabetes and hypertonic saline administration. Chronically increased ANP may prevent renal accumulation of platinum in the kidney.     

The defensive role of taurine against gonadotoxicity and testicular apoptosis effects induced by cisplatin in rats

IntroductionCisplatin (CIS), which is used as a therapeutic antineoplastic agent may produce gonadotoxicity in a process linked to chemotherapy. Taurine, through its potential antioxidant effect, has a protective role against cisplatin-induced oxidative stress and apoptosis.ObjectiveTo investigate whether taurine intake can ameliorate testicular damage induced by cisplatin and to study the possible mechanism that mediates this action, either through its antioxidant action alone or in addition to its anti-apoptotic effects.Patients and methodsFifty healthy adult white male albino rats were randomly distributed into five groups, each involving ten animals. The first group represents the negative control group. The other four groups received three equal doses (3 mg/kg body weight) intraperitoneal injections of cisplatin on alternate days. In the positive control group (group 2), saline only was given. Groups 3, 4 &5 received taurine in distilled water at oral doses of 50, 150, 250 mg/kg, respectively, on alternate days followed by cisplatin (each injection of cisplatin was given 1 day after taurine).On the 28th day after the first dose of normal saline, cisplatin or taurine, blood samples were examined for testosterone levels. All rats were killed and their testes were examined.ResultsRats treated with cisplatin alone showed reduced body weight in addition to reduced testicular weight, impaired sperm counts, and oxidative stress (reduced GSH, increased MDA level), decreased plasma testosterone, apoptotic marker (increased Bax, decreased bcl2). However following taurine induction, the figures for GSH and MDA changed significantly (P < 0.005) referring to the effect of taurine as a potent antioxidant.ConclusionsCisplatin-induced germ cell apoptosis may result in decreasing spermatogenesis. However, taurine could effectively prevent nearly all of these cisplatin-induced testicular abnormalities, thereby proving to be an effective cytoprotectant.     

Differential acute effects of aldosterone, dexamethasone, and hyperkalemia on distal tubular potassium secretion in the rat kidney

To determine the specific effects on renal potassium transport of acute elevations in plasma aldosterone, dexamethasone, and potassium concentrations, we studied adrenalectomized rats prepared such that each factor could be varied independently. Clearance data alone could not be used to deduce the underlying tubular transport effects, however, since infusion of each of these agents was associated with a marked change in urinary flow rate, which may itself have influenced potassium excretion. We therefore used a technique of continuous microperfusion, in vivo, of single superficial distal tubules to evaluate potassium secretion at constant luminal flow rate during each experimental maneuver. Acute aldosterone infusion was associated with a 90% stimulation of potassium secretion by microperfused tubules. However, total kidney sodium excretion and urinary flow rate were markedly reduced, and these factors opposed the direct tubular action of aldosterone, resulting in no net change in the amount of potassium excreted into the final urine. Conversely, dexamethasone had no direct effect on potassium secretion by single microperfused tubules, but it caused a sharp increase in urinary flow and sodium excretion, and secondarily enhanced urinary potassium excretion by 50%. Hyperkalemia per se stimulated renal potassium excretion both via a direct tubular effect and by increasing urinary flow rate. We conclude that urinary potassium excretion after infusion of each of these agents represents the net result of direct tubular effects and secondary flow-mediated changes.     

Renal toxicity of cadmium-metallothionein and enzymuria in rats

The mechanism of cadmium metallothionein (Cd-MT)-induced renal toxicity was studied in rats using urinary enzyme excretion as a marker for cellular damage. Animals were injected with either saline or Zn (20 mg of Zn as ZnSO4/kg b.wt.) at 0.5, 4 or 24 hr before injection of Cd-MT (0.3 mg of Cd as Cd-MT/kg b.wt. i.p.). Activities of two brush border enzymes, alkaline phosphatase (ALP) and gamma-glutamyl-transpeptidase (GGT), and a lysosomal enzyme, N-acetyl-beta-D-glucosaminidase (NAG), were measured in 24-hr urine collections. Urinary excretion of all three enzymes was increased significantly after Cd-MT injection. Both ALP and GGT excretions reached a maximum at 24 hr whereas NAG excretion reached peak values at 48 hr after Cd-MT injection. The excretion of all three enzymes decreased to the control level by the 3rd day. Zn pretreatment alone had no effect on urinary enzyme excretion. Pretreatment with Zn salts at 0.5 and 2 hr before Cd-MT injection did not show any difference in the urinary excretion of the enzymes as compared with the saline-treated controls. However, injection of Zn salts at 24 hr before Cd-MT injection resulted in a significant decrease in the excretion of the lysosomal enzyme NAG whereas both ALP and GGT excretions were unchanged. Extensive proximal tubular damage was observed morphologically in all the rats injected with Cd-MT, but the cellular damage was less in rats pretreated with Zn sulfate 24 hr before Cd-MT injection.(ABSTRACT TRUNCATED AT 250 WORDS)     

实验性2型糖尿病肾病大鼠模型研究

目的建立2型糖尿病肾病大鼠模型。方法雄性Wistar大鼠高糖高脂喂养8周后,腹腔注射链脲佐菌素（STZ,30mg／kg）诱导糖尿病大鼠。通过葡萄糖耐量试验和胰岛素抵抗指数判断胰岛素抵抗情况。结果在注射STZ之前,高糖高脂喂养大鼠和对照组血糖基本相似,而血清胰岛素水平明显高于对照组。在注射STZ之后,高糖高脂大鼠血糖明显增高,血清胰岛素降至对照组水平。在第10周末,2型糖尿病大鼠体重、血压、胆固醇、甘油三酯、24小时尿蛋白定量和肾重指数较对照组存在差异而肾功无明显差异。。肾脏病理显示2型糖尿病大鼠具有典型2型糖尿病肾病的病理改变。结论联合高糖高脂饮食和小剂量STZ方法建立的动物模型可以用于2型糖尿病肾病的研究。     

The protective effect of melatonin on cisplatin nephrotoxicity

Regarding the mechanisms of cisplatin (CP) nephrotoxicity, several hypotheses have been put forward, among which oxidative stress (including depletion of glutathione and production of lipid peroxide) is noticeable. This investigation elucidates the role of the antioxidant system in CP-induced nephrotoxicity and the nephroprotection by melatonin. Balb/c mice were injected i.p. with: 1) vehicle control; 2) a single dose of 6.5 mg/kg cisplatin, CP group; 3) melatonin in a dose of 10 mg/kg for 5 days after CP injection, CP-M group; 4) melatonin (10 mg/kg) for 5 days before and after CP injection, M-CP-M group; 5) melatonin in a dose of 10 mg/kg for 5 days, M group. Mice were sacrificed 5 days after CP injection to determine blood urea nitrogen (BUN) and serum creatinine. Renal lipid peroxidation (LP) and glutathione (GSH) levels were evaluated in kidney homogenates. Cisplatin administration resulted in increased LP, BUN and serum creatinine levels and decreased GSH levels, whereas melatonin reversed these effects. Morphological kidney damage was apparent in the CP group. Mentioned degeneration was moderate in the CP-M group, whereas morphological findings of the M-CP-M group implied a well preserved kidney tissue. When M was administered alone, it didn't cause any significant change in biochemical parameters. Both C and M groups exhibited similar biochemical and morphological findings in light and transmission electron microscope observation. In conclusion, the present study suggests that melatonin may be of therapeutic benefit when used with CP.     

链脲佐菌素诱导的糖尿病大鼠尿podocalyxin排泄的动态变化

目的观察链脲佐菌素(STZ)诱导的糖尿病大鼠足细胞标志蛋白podocalyxin随尿排泄的动态变化并探讨其意义。方法 STZ 65 mg/kg腹腔注射后建立糖尿病大鼠模型,正常大鼠注射等量枸橼酸缓冲液作为对照组(NC组)。分别于0周、2周、4周和8周监测两组大鼠血糖、尿白蛋白(UALB)及尿沉渣中PCX含量(UPCX)和8周末HbA1c,为消除尿量影响分别用尿肌酐(UCr)校正称为UACR(UALB/UCr)及UPCR(UPCX/UCr)。结果 (1)与健康对照组比较,糖尿病大鼠各时间点血糖和8周时HbA1c显著增高,P<0.01;(2)与健康对照组比较,2周时糖尿病大鼠UACR及UPCR即显著增高,并随时间不断增长;(3)糖尿病大鼠UPCR与UACR呈正相关(r=0.86,P<0.01)。结论足细胞损伤参与糖尿病肾脏病变的发生,尿PCX检测可作为反映糖尿病早期肾损害的指标之一。     

Prevention of nephrotoxicity of cisplatin by repeated oral administration of ebselen in rats

The ability of ebselen, which exhibits glutathione peroxidase (GSH-Px)-like activity, to prevent cisplatin (CDDP)-induced nephrotoxicity was examined in rats. CDDP (6 mg/kg [20 micromol/kg] body weight) was injected intraperitoneally. In subgroups, daily ebselen doses of 2.75 (10 micromol), 5.5 (20 micromol), or 11.0 mg (40 micromol)/kg body weight were administrated orally 1 hour prior to CDDP treatment. Treatment with CDDP alone resulted in significantly increased plasma creatinine (Cr) and blood urea nitrogen (BUN) levels. Repeated administration of 5.5 and 11.0 mg/kg ebselen prevented the CDDP-induced elevation of plasma Cr and BUN levels and protected against kidney damage. Relative to controls, rat that received CDDP treatment displayed a decreased ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), an indicator directly related to oxidative stress, and elevated malondialdehyde (MDA) levels in the kidney. In comparison with controls, activity of GSH-Px activity, which antioxidant enzyme, was also reduced in the kidney of rats treated with CDDP. Repeated administration of 5.5 or 11.0 mg/kg ebselen prevented CDDP-induced alteration of GSH/GSSG ratios, MDA levels, and GSH-Px activity; however, no protection against CDDP was observed with administration of 2.75 mg/kg ebselen. Effective protection of CDDP-induced nephrotoxicity with ebselen was observed only when the molar amount of each daily ebselen treatment equaled or exceeded     

The relationship between parameters of serotonin metabolism and emetogenic potential of platinum-based chemotherapy regimens

 Evaluation of the relationship between parameters of serotonin (5-HT) metabolism and emesis in platinum-based chemotherapy. Female patients receiving chemotherapies containing either cisplatin (35 patients; 80 courses) or carboplatin (65 patients; 102 courses) were recruited. Recording of emesis and measurements of urinary 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of 5-HT, was performed over 3 days. Comparisons were performed for single-agent cisplatin (DDP) versus single-agent carboplatin (CBDCA), single-agent high-dose DDP (≥75 mg/m²) versus high-dose DDP combined with cyclophosphamide, high-dose versus low-dose DDP (≤50 mg/m²), and single-agent CBDCA versus a combination with alkylating agents. Cisplatin induced both a significantly higher frequency of emesis and a significantly higher increase of 5-HIAA excretion than carboplatin. The velocity of 5-HIAA increase may correlate better with emetogenic potential than peak 5-HIAA excretion levels. The increase of 5-HIAA excretion induced by cisplatin was limited to day 1. Higher cisplatin doses showed both a higher emetogenic potential and a more pronounced increase in urinary 5-HIAA on day 1. No significant difference was found when single-agent cisplatin was compared with cisplatin combined with cyclophosphamide. In contrast, a combination of carboplatin with alkylating agents induced a larger increase in urinary 5-HIAA and showed a higher emetogenic potential than single-agent carboplatin. Low-dose cisplatin induced less emesis than carboplatin combination therapy, but induced a larger increase in urinary 5-HIAA. Our findings provide evidence for a relationship between emetogenic potential and patterns of 5-HIAA excretion following platinum-based chemotherapy.     

Effects of exercise and grape juice ingestion in combination on plasma concentrations of purine bases and uridine

BACKGROUND: Since grape juice contains considerable amounts of fructose, which may increase the plasma concentration of urate, the combination of exercise and grape juice may increase the plasma concentration of urate to a greater degree than grape juice or exercise alone. METHODS: We performed 3 experiments with 6 healthy male Japanese. The first was exercise alone (exercise alone experiment), the second was grape juice ingestion alone (grape juice alone experiment), and the third was a combination of exercise and grape juice ingestion (combination experiment). RESULTS: In the exercise alone experiment, the concentrations of purine bases and uridine in plasma, and lactate in blood, as well as the urinary excretion of oxypurines were increased, whereas the urinary excretion of uric acid and fractional excretion of purine bases were decreased. In the grape juice alone experiment, the concentrations of purine bases and uridine, as well as lactate in blood were increased, whereas the fractional excretion of uric acid was decreased. In the combination experiment, the concentrations of purine bases and uridine in plasma, and lactate in blood, as well as the urinary excretion of oxypurines were increased, whereas the urinary excretion of uric acid and fractional excretion of hypoxanthine, xanthine, and uric acid were decreased. The increase in plasma concentration of urate by the combination of exercise and grape juice was greater than that by each alone, though it was not significantly different from the sum of increases in those 2 experiments. CONCLUSION: Increases in adenine nucleotide degradation and lactic acid production caused by both exercise and grape juice ingestion play an important role in the increase in plasma concentration of urate, while those in combination have an additive effect on that concentration.     

Pharmacokinetics of SCE-1141, a stereoisomer of cefmenoxime, in rats

The pharmacokinetic properties of SCE-1141, an anti stereoisomer of cefmenoxime, were compared with those of cefmenoxime. SCE-1141 levels in plasma and tissues peaked at 30 min after the intramuscular administration of 20 mg/kg; the plasma level declined with a half-life of about 18 min. The area under the concentration-time curve in plasma and the half-life after intravenous administration were similar to those after intramuscular administration. SCE-1141 was distributed at high concentrations in the liver and kidney of normal rats, and at lower concentrations in the liver of rats with acute liver impairment. SCE-1141 levels in plasma and tissues, except liver, were lower than those of cefmenoxime. The 24-h biliary and urinary excretions of SCE-1141 were 73% and 26% of the dose, respectively; these were significantly different from those of cefmenoxime: 33% in bile and 55% in urine. In rats with acute liver impairment, the biliary excretion of SCE-1141 was decreased, and the urinary excretion increased.     

Interaction of cisplatin and carboplatin with sodium thiosulfate: reaction rates and protein binding

Toxicity of cisplatin can be decreased by concomitant administration of sodium thiosulfate, which perhaps chemically inactivates this platinum compound. We studied the disappearance of cisplatin and carboplatin in aqueous solutions of thiosulfate at 37 degrees C by means of liquid chromatography. At initial concentrations that were similar to therapeutic concentrations in plasma, both drugs disappeared, with half-lives of 66 and 537 min for cisplatin and carboplatin, respectively. At higher thiosulfate concentrations, as found in urine, the respective half-lives were 3.7 and 33.8 min. These values suggest that direct chemical interaction in the plasma compartment has limited therapeutic consequences, whereas the anti-toxic effect of thiosulfate might be explained by the rapid inactivation of cisplatin in the kidneys. Reaction products of cisplatin and thiosulfate bound instantaneously and mainly reversibly to plasma proteins. Protein-bound cisplatin was not released by added thiosulfate--which may explain why thiosulfate, to be effective, must be given in advance of and during cisplatin administration.     

Glucocorticoids and 11 beta-hydroxysteroid dehydrogenase type 2 gene expression in the aging kidney

BACKGROUND: Aging is associated with increased concentrations of circulating glucocorticoids, a situation expected to induce a glucocorticoid-mediated mineralocorticoid effect, resulting in sodium retention and hypertension unless counteracting mechanisms are operative. Conversion of glucocorticoids to inert 11 beta-keto compounds by the enzyme 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) is one of these mechanisms. We hypothesized therefore that 11 beta-HSD2 gene expression and/or activity increase with age in male WAG/Rij rats, a strain without increased blood pressure with age or senescence-related obesity or kidney disease. MATERIALS AND METHODS: Corticosterone (B) concentrations in plasma and urinary excretion of corticosterone and dehydrocorticosterone (A) tetrahydro metabolites, THB + 5 alpha-THB + THA, were assessed by gas chromatography-mass spectrometry (GC-MS) in 10-month-old-rats (n = 6) and in 30-month-old rats (n = 6). Renal 11 beta-HSD2 messenger ribonucleic acid (mRNA) abundance was measured by real-time quantitative TaqMan polymerase chain reaction and microarray assays. RESULTS: Thirty-month-old rats had significantly higher corticosterone concentrations in plasma and increased urinary excretion of corticosterone and dehydrocorticosterone tetrahydro metabolites. Conversion of B to A in kidney microsomes from 30-month-old rats was moderately but not significantly increased compared with 10-month-old rats. The urinary ratios of (THB + 5 alpha-THB)/THA and free B/A and renal 11 beta-HSD2 mRNA abundance were equal in 10- and 30-month-old rats. CONCLUSIONS: There is no evidence for an enhanced gene expression or activity of renal 11 beta-HSD2 in these aging rats, suggesting either that endogenous 11 beta-HSD2 is able to cope with the increased corticosterone concentrations characteristic of the aging process or that alternative mechanisms contribute to the maintenance of a normal sodium excretion in these animals.     

The beneficial effects of pancreas transplant alone on diabetic nephropathy

OBJECTIVE: Pancreas transplant alone can be effective in significantly improving the quality of life of type 1 diabetic patients, and it can also eliminate acute diabetes complications, such as hypoglycemic and/or hyperglycemic episodes. The effects of pancreas transplant alone on long-term complications of diabetes, including nephropathy, are still not settled. We evaluated whether restoration of long-lasting normoglycemia by pancreas transplant alone might have beneficial action on diabetic nephropathy. RESEARCH DESIGN AND METHODS: A total of 32 type 1 diabetic patients were evaluated before and 1 year after successful pancreas transplant alone, together with 30 matched nontransplanted type 1 diabetic subjects. Several metabolic and kidney function parameters were measured, including plasma glucose, glycohemoglobin (A1C), C-peptide, plasma lipids, blood pressure, creatinine, creatinine clearance, and urinary protein excretion. RESULTS: Pancreas transplant alone restored sustained normoglycemia, without exogenous insulin administration, and improved plasma lipid levels. Blood pressure decreased significantly. Creatinine concentrations and clearances did not differ before and after transplantation. Urinary protein excretion decreased significantly after pancreas transplant alone, with four microalbuminuric and three macroalbuminuric patients who became normoalbuminuric. None of these changes occurred in the nontransplanted group. CONCLUSIONS: Successful pancreas transplant alone, through restoration of sustained normoglycemia, improves diabetic nephropathy in type 1 diabetic patients.     

Renal secretion of phenolsulfonphthalein: analysis of its vectorial transport in normal and mutant analbuminemic rats

Transtubular transport of many organic anions, such as p-aminohippuric acid and phenolsulfonphthalein (PSP), from plasma into urine is an important renal function. Most of these nephrophilic ligands strongly bind to albumin in the circulation. To investigate a possible function of plasma albumin in vectorial transport of these organic anions, plasma clearance and urinary excretion of PSP, on one hand, and its interaction with serum proteins, on the other, were studied in normal and mutant Nagase analbuminemic rats (NAR). Intravenously administered PSP rapidly disappeared from the circulation, followed by its urinary excretion in both NAR and normal rats. However, its plasma clearance was significantly larger in NAR (53.9 ml/min/kg body weight) than in normal animals (4.7 ml/min/kg body weight). Gel exclusion Sephadex G-100 chromatography and ultrafiltration analysis revealed that the PSP binding capacity of serum proteins was considerably lower in NAR than in normal rats; 32.0% and 12.5% of the ligand bound to NAR serum protein and 94.4% and 84.2% to normal rat serum protein (predominantly albumin) at 0.1 and 0.5 mmol/L ligand concentrations, respectively. Despite the greater PSP clearance in NAR, its urinary excretion was lower in NAR than in the normal animals; 20.9% +/- 2.5% and 46.0% +/- 12.6% of the administered dose appeared in NAR and normal rat urine, respectively, within 3 hours of administration. Injection of PSP with equimolar albumin resulted in a decrease in plasma clearance and an increase in urinary excretion of PSP in NAR; more than 31.4% +/- 3.3% of the injected dose appeared in the urine within 3 hours of administration.(ABSTRACT TRUNCATED AT 250 WORDS)