The effect of dietary protein restriction on high dose gentamicin nephrotoxicity in rats.

Gentamicin (120 mg/kg/day) was administered for 10 days to Sprague-Dawley rats given either a low (5% w/w) or normal (18% w/w) protein diet. Serum protein concentrations remained normal in all rats during the study. Nephrotoxicity was slightly less severe in rats fed a low protein diet as shown by: (i) a mean creatinine clearance rate (14 +/- 4 ml/min) which was significantly greater than that (8 +/- 3 ml/min) recorded from the rats maintained on the normal diet (P less than 0.05); (ii) lower activities of urinary N-acetyl-beta-D glucosaminidase (NAG); and (iii) less marked histological changes. Mean tissue concentrations of gentamicin were considerably lower in both renal cortex and medulla from rats maintained on the low protein diet than from those animals on the normal diet (P less than 0.01 and P less than 0.05, respectively). These differences were, however, not reflected in the mean trough serum gentamicin concentrations which were not significantly different between the two groups. These results are discussed in relation to the proposed mechanisms involved in gentamicin-induced nephrotoxicity.     

The effect of dietary restriction on thymus autonomy

Fifty percent dietary restriction allows for continued body growth in young animals, whereas in older animals this dietary regime resulted in a 25% drop in body weight over a 10-wk period. This resulted in a relatively low rate of mitosis in the thymus tissue from young animals so that thymus size was maintained in proportion with body weight. There was no evidence to suggest that the thymus glands from dietary restricted young animals could not maintain their role in immune function. In the older animals dietary restriction resulted in depletion of thymic lymphocytes, despite a relatively high rate of cell division. It is postulated that this may be a result of stress caused by the dietary regime.     

Dopamine protects gentamicin early induced nephrotoxicity in Sprague–Dawley rats

Routine therapeutic use of dopamine has been shown to influence renal hemodynamic response through removing contractile effects of nephrotoxicants on mesangial cells and subsequent interaction with locally expressed prostaglandin subtypes (PGE2 and PGI2). To determine the way in which the amino acid managed to preserve Sprague–Dawley rats against gentamicin-induced nephrotoxicity, a randomized prospective study was carried out. In this study, 40 healthy rats were randomly assigned in four trials to receive either normal saline, gentamicin, gentamicin plus dopamine, or dopamine for 9 days. Administration of gentamicin at a dose of 80 mg kg⁻¹ day⁻¹ reduced the creatinine clearance as result of early hemodynamic toxicity, and tubular reabsorption of electrolytes after phospholipiduria and urinary activity of tubular enzymes. H&E histopathology revealed acute tubular necrosis with cast formation triggered by gentamicin over 9 days of experiment, in addition to interstitial nephritis and tubular epithelial loss. Further biochemical studies showed protecting effects of supplemented dopamine, including slow down in the urinary enzyme activity, modest to moderate phospholipiduria with recovery in the renal clearance and the ATPase activity up to 50% when compared to saline- and gentamicin-treated rats. Normal glomerular and tubular function on recovery from toxic renal failure led us to conclude that renovascular effects of dopamine were early attributed to glomerular preservation, whereas the tubule function prepared by the amino acid was just a consequent.     

A light and electron microscopic analysis of gentamicin nephrotoxicity in rats.

The sequence of proximal tubular damage and repair after gentamicin sulfate administration was studied by light and electron microscopy in Fischer 344 rats. The drug was administered at a dose of 40 mg/kg for up to 14 days. Although epithelial destruction was progressive with time, the extent and degree of tubular damage varied among animals at each interval. Tubule regeneration began to occur by the tenth day despite continued drug administration. Regenerating cells appeared to originate from residual epithelial cells in areas of tubular damage. The morphologically immature regenerating cells are apparently metabolically immature as well and appear not to be susceptible to toxic effects of the drug. Tubules were repopulated by 3 days following cessation of gentamicin administration. Except for foci of tubular atrophy and interstitial fibrosis, cortical tissues were comparable to controls ultrastructurally at the end of 31 days.     

The effect of dietary restriction on mouse T cell functions

Forty percent dietary restriction on 9-weeks-old C3H/He mice caused decrease of the weight of central lymphoid organs in parallel with the reduction of body weight. However, the percentage of splenic T cells was dramatically increased in diet-restricted mouse spleen cells. Generally, normal mouse spleen cells contained about 30% of Thy 1.2+ T cells, but the restricted mouse spleen cells contained 80% Thy 1.2+ T cells. Ly 1+, L3T4+ T cells, but not Ly 2+ T cells, also increased in diet-restricted mouse compared with the unrestricted mice. In parallel with the dramatic changes of splenic T cells, spleen cells obtained from diet-restricted mice showed higher immunological responses against alloantigen and interleukin 2. It was also demonstrated than nylon-passed splenic T cells obtained from diet-restricted mice showed higher levels of T cell responses against r-IL-2 and alloantigen, indicating that dietary restriction modulates T cell functions themselves.     

Therapeutic effect of cimetidine on acetaminophen-induced nephrotoxicity in rats

Acetaminophen as an analgesic and antipyretic drug can induce renal toxicity in high doses. Cimetidine as an H₂-blocker can inhibit the cytochrome P450 enzymes and reduce the toxic effect of acetaminophen on renal tissue. Eighty rats in eight groups comprising normal control group, acetaminophen control group, cimetidine control group, and five different treatment groups (cimetidine was administrated at 0, 1, 2, 4, and 8 h after acetaminophen administration) were used. Acetaminophen was administered at a toxic of dose 3 g/kg orally, and cimetidine (12.5 mg/kg) was administrated by intraperitoneal route at different times after induction of toxicity. Creatinine and urea were measured, and pathologic lesions were determined. In treatment groups 3 and 6, the urea and creatinine concentration showed no significant difference from group 1. In other treatment groups, the urea and creatinine concentrations were increased significantly (p < 0.05). Histopathologic changes in group 6 were mild in comparison to other groups. We concluded that administration of cimetidine at least 2 h after acetaminophen toxicity can reduce renal lesions.     

The protective effect of nitrendipine on gentamicin acute renal failure in rats

Aminoglycoside nephrotoxicity was produced in two groups of Fischer rats by intraperitoneal injection of gentamicin, 40 mg/kg/day for 2 weeks. Beginning 3 days prior to, and continuing throughout the 2-week treatment period, one of the groups (control) received the inert vehicle, polyethylene glycol, while the experimental group was given nitrendipine, a calcium channel blocker, in a dose of 25 mg/kg/day by gavage. Both groups received food and water ad libitum. Gentamicin with vehicle caused a marked decrease in inulin clearance (4.9 ml/min/kg) and paraaminohippurate (PAH) extraction (26%), and extensive renal tubular necrosis. In comparison, the nitrendipine-treated rats had a significantly increased clearance (9.8 ml/min/kg) and PAH extraction (48%), and less histopathologic damage. Renal tissue content of gentamicin was not influenced by nitrendipine after 4 days of dosing. Nitrendipine, a diisopyridine derived calcium channel blocker, offers significant functional and histologic protection against aminoglycoside nephrotoxicity in Fischer rats. Its mode of action in this regard is unknown.     

Urinary myelin figures in gentamicin nephrotoxicity.

The nephrotoxicity of gentamicin is associated with formation of myelin figures within the proximal convoluted tubules of experimental animals and man. By electron microscopy, the authors studied urinary sediments of patients who were treated with gentamicin to detect the occurrence of myelin figures. All three patients who had renal impairment and were treated with gentamicin had numerous urinary myelin figures. By contrast, myelin figures were not observed in urinary sediments of four patients who had no renal impairment despite gentamicin therapy, or nine patients who had no renal impairment and did not receive gentamicin therapy. Occasional myelin figures were detected in a urinary sediment of one of eight patients who had renal impairment and no gentamicin therapy. When the urinary sediments of patients who had gentamicin nephrotoxicity were compared with those of patients with Fabry disease, morphologic differences between the myelin figures of the two groups were detected. The study demonstrates the presence of myelin figures in urines of patients with acute renal failure receiving gentamicin, and suggests that the finding of these myelin figures within urine samples may contribute to the diagnosis of gentamicin-induced nephrotoxicity.     

Effect of dietary restriction on lysosomal bodies and total protein synthesis in hepatocytes of aging rats.

The accumulation of lysosomal bodies has long been considered to be an important correlate of aging. However it is not well established whether these age related changes interfere with cellular function. In this study, an evaluation of lysosomes by ultrastructural analysis was performed in livers of 4-6 and 20-24-month-old Sprague-Dawley female rats, fed ad libitum (A) or a restricted diet (R). An attempt was made to relate this parameter to hepatic protein synthesis, a liver function known to decrease with age and increase with dietary restriction. Aging was accompanied in both A and R animals with higher number and size of secondary lysosomes (lipofuscin) and by a decrease in total protein synthesis in hepatocytes. When compared to age matched ad libitum fed animals, livers of food restricted rats contained higher number of secondary lysosomes, yet exhibited higher protein synthetic capacity. Thus in hepatocytes, lipofuscin accumulation does not seem to interfere with cellular function.     

Effects of dietary sodium restriction on heart rate control in rats

The effects of dietary sodium restriction on heart rate control were evaluated in male Wistar rats maintained for 4 wk on a low- (22 meq/kg diet) or standard (141 meq/kg diet) sodium diet. In conscious low-sodium rats, atropine produced heart rate increases greater than in standard sodium animals, indicating that basal parasympathetic tone was elevated. Sodium restriction did not affect basal sympathetic tone, since similar reductions in heart rate were produced by propranolol in both dietary groups. However, sympathetically mediated tachycardic responses to sodium nitroprusside were augmented in low-sodium rats. This enhancement of sympathetic function was also observed in low-sodium animals after pithing. The increases in heart rate produced by spinal sympathetic stimulation were significantly accentuated; whereas, responses to norepinephrine were not affected by the diets. This finding is in agreement with the observation that the chronotropic responses elicited by isoproterenol in isolated atria were not altered. When neuronal influences on heart rate were blocked by combined administration of atropine and propranolol or chlorisondamine in conscious rats, the underlying intrinsic cardiac rate was found to be significantly higher in low-sodium rats. In summary, the present study identifies three effects of sodium restriction on heart rate control in the rat: 1) basal parasympathetic tone is increased, 2) heart rate responses to sympathetic activation are enhanced, and 3) the intrinsic cardiac rate is elevated.     

The relative protective effects of moderate dietary restriction versus dietary modification on spontaneous cardiomyopathy in male Sprague-Dawley rats

The relative protective effects of modifying dietary protein, fat, fiber, and energy content vs moderate food or dietary restriction (DR) on spontaneous cardiomyopathy of Charles River male Sprague-Dawley (SD) rats was evaluated at 1 and 2 years. For 2 years, SD rats were fed Purina Rodent Chow 5002 (21.4% protein, 5.7% fat, 4.1% fiber, 3.1 kcal/g) or a modified rodent chow 5002-9 (13.6% protein, 4.6% fat, 15.7% crude fiber, 2.4 kcal/g) ad libitum (AL) or by moderate DR at approximately 65% of the caloric intake of the AL group fed the 5002 diet. Serum lipids, carcass composition, and organ weights were evaluated and hearts were qualitatively and quantitatively examined microscopically for male SD rats at 1 and 2 years. Cardiomyopathy was characterized by the colocalization of myocardial degeneration, the development of subepicardial, perivascular, subendocardial, and interstitial fibrosis, and mononuclear inflammatory cell infiltration that increased by incidence and severity in an age-dependent manner from 1 to 2 years. SD rats fed the 5002 diet AL had the greatest heart weights and the most severe cardiomyopathy, with the highest myocardial fibrotic index. These parameters were relatively decreased in the AL 5002-9 diet, the DR 5002 diet, and the DR 5002-9 diet rats at 1 and 2 years. Regardless of the type of diet fed, both AL groups had the most severe cardiomyopathy by 2 years. Moderate DR allowed isocaloric comparisons of the relative effects of modified diets on survival, obesity, and heart disease. Only slight improvements in the severity and progression of spontaneous cardiomyopathy were seen by modification of the protein, fiber, fat, and energy content of the diet if fed AL. However, moderate DR with either diet was more effective than changing the diet composition in preventing and controlling the progression of cardiomyopathy in male SD rats.     

Differential effect of NDGA on cisplatin-induced nephrotoxicity in Spargue-Dawley rats

Context: Nephrotoxicity is a highly manifested complication in cancer patients undergoing cisplatin therapy. Oxidative stress, nitrosative stress, and inflammation are the major patho-mechanisms of cisplatin-induced nephrotoxicity.

Objective: The purpose of this study was to determine the protective effect of pretreatment and post-treatment of nordihydroguaiarectic acid (NDGA) on cisplatin-induced nephrotoxicity.

Material and methods: Cisplatin-induced renal damage was accessed by biochemical estimation of nephrotoxicity markers, oxidative and nitrosative stress whereas inflammatory markers were accessed by ELISA technique.

Results and conclusion: Cisplatin administration had resulted in renal injury associated with oxidative stress, nitrosative stress as evident by increased MDA, ROS, and nitrite level with decreased antioxidants such as SOD, catalase and, glutathione. Furthermore, cisplatin treated animals exhibited a noticeable pro-inflammatory response with the substantial increase in renal levels of TNF-α, IL-1β, and IL-6 and decrease in the renal level of IL-10. NDGA pretreatment did not lead to significantly rise in oxidative stress, nitrosative stress, and inflammation along with restored the level of IL-10 in the kidney and preserved renal function. Moreover, NDGA post-treatment also presented nephroprotective effects, but the effects were not as positive as compared to NDGA pretreatment. In conclusion, these results indicate that NDGA pretreatment is renoprotective while on the other hand NDGA post-treatment is not so effective in cisplatin-induced nephrotoxicity.     

Dietary protein level alters gentamicin-induced nephrotoxicity in rats

Aminoglycosides (AG) such as gentamicin are antimicrobial drugs widely used in the hospital setting due to their efficacy in the treatment of severe gram-negative bacterial infections. However, all AG have the potential to cause nephrotoxicity. Two studies have been conducted (1) to assess the protein level of a diet that would give the best renal outcome with gentamicin administration, and (2) to get a better idea about the rhythms of food ingestion associated with the different protein levels. Adult female Sprague–Dawley rats fully adapted to a standard chow diet, the standard chow with 20% or 55% added casein were chronically treated for 10 days with a nephrotoxic dose of gentamicin sulfate (40 mg/kg/day, i.p.) or a saline solution. Food ingestion patterns of rats were recorded every hour using a Diet Scan system and gentamicin nephrotoxicity indices were measured. The second study used rats that were fed the same diets and given a sham injection. Corticosterone was assayed to quantify the stress of the animals. Results showed that chronic gentamicin treatment leads to a decrease in food intake and flattening of the rhythms of food ingestion. Also, chow feeding and the 20% casein diet were found to be more protective against gentamicin-induced nephrotoxicity than the 55% casein diet. Therefore, while a protein-rich diet can be protective against gentamicin-induced nephrotoxicity, the present study demonstrates that a diet too high in protein might rather be harmful to the kidneys.     

Long-term dietary restriction causes negative effects on cognitive functions in rats

Long-term dietary restriction is reported to increase life span and improve age-related cognitive deficits. The present study shows that the restriction increases the life span of rats but decreases their cognitive ability. Thirty-two rats were divided into restricted and ad lib feeding groups at 2.5 months of age. The restricted rats were kept at a weight of 280g. The restricted rats were poor in performing the Morris water maze task at 7-12 months. At 17-18 months, they were poor in performing the delayed matching-to-place task. At 24-27 months, the surviving 13 restricted and 5 ad lib rats performed the spatial discrimination task. The restricted rats were also poor in performing this task. Injection of glucose prior to the discrimination task improved their performance to the level of the ad lib rats. These results suggest that dietary restriction is beneficial for longevity but has negative effects on the performance of cognitive tasks, and that the cause of the negative effects may be a reduced availability of glucose in the food-restricted aged rats.     

碱性成纤维细胞生长因子对庆大霉素肾毒性防治研究中细胞超微结构的影响

目的　探讨碱性成纤维细胞生长因子 (bFGF)对庆大霉素 (GM)肾毒性防治研究中一些细胞超微结构的改变。方法　实验分两部分 :(1)保护研究 :实验动物为豚鼠 ,随机分为对照组和实验组 (每组n =10 )。对照组按 80mg·kg·d-1肌注GM17d ,停药后继续注射生理盐水 (NS) 6d ;实验组注射GM的同时 ,加注 2 0 0 0U·kg-1·d-1bFGF 17d ,停GM后继续注射bFGF 6d。(2 )治疗研究 :实验动物为雄性Wistar大鼠 ,随机分为对照组和实验组 (每组 n=10 ) ,两组动物均按 16 0mg·kg-1·d-1肌注GM 9d ;实验组于第 10d按 2 0 0 0U·kg-1·d-1肌注bFGF 9d ,而对照组则注射NS。所有动物均取肾皮质制片 ,电镜观察。结果　两部分研究中对照组电镜下均可见肾小管上皮细胞胞质染色较淡 ,细胞内脂滴、包含物增多 ;线粒体、溶酶体、微绒毛等细胞器或细胞微细结构改变。实验组电镜下肾小管上皮细胞形态基本正常 ,治疗实验组中还可见较多增生的近端和远端小管。结论　bFGF对庆大霉素毒性作用所造成的肾小管损伤有很好的防治作用     

Age-dependent influence of dietary zinc restriction on short-term memory in male rats

Zinc is an essential micro-nutrient involved in numerous physiological functions. The high content of zinc in the hippocampus, coupled with the integral involvement of the hippocampus in memory, strongly implicates zinc in memory processing. The hypothesis of the current study was that dietary zinc restriction influenced short-term memory in postweaned rats, and this influence was age-dependent. Male rats (43 days to 18 months old) were divided into five experimental groups based on age, and fed zinc-adequate (zinc at 20 mg/kg as zinc chloride) or zinc-deficient (zinc less than 1-2 mg/kg) diets for a minimum of 3 weeks. Short-term memory was assessed using the distal-cue version of the Morris water maze (MWM). All rats fed the zinc-restricted diet exhibited cyclic anorexia, decreased weight gain, and significantly lower liver and femur zinc concentrations compared to age-matched controls. Further, whole brain, hippocampal, and cerebral wet weights were significantly reduced in the zinc-restricted treatment groups of all the age groups. Only zinc-restricted rats that were less than 62 days of age at the start of zinc restriction demonstrated significantly prolonged escape latencies in the water maze, indicating deficits in short-term memory. Regression analyses confirmed that the short-term memory deficits were correlated with significantly lower hippocampal and cerebral zinc concentrations compared to age-matched control and pair-fed rats. These results emphasize the significance of a critical age of influence for dietary zinc in memory processing, and the importance of considering age when studying zinc nutriture and CNS function.     

Experimental atherosclerosis in swine: effect of dietary protein and high fat

Two groups of pigs each consisting of 6 animals were fed for 18 months on isocaloric amounts of an experimental diet with a high fat content and cholesterol but with widely different levels of protein (5% vs. 25% by weight of the diet). In addition, a third group consisting of 4 animals was maintained on normal stock diet to serve as control.Animals of the low protein group showed the maximal intimal surface area involvement with atherosclerotic lesions in the aorta and coronary arteries, and also the most severe among the three groups. No significant differences were noted in the extent and severity of lesions between the high protein-high fat fed animals as compared with the high protein-low fat fed controls. Lesions of the low protein group had a higher cholesterol content and a raised cholesterol:phospholipid ratio than those in the other two groups.Extremely low levels of dietary proteins seem to have had a promotive effect on the induction of atherosclerotic lesions by an atherogenic diet, whereas adequate levels of dietary proteins have had a protective influence. The precise mechanism by which varying levels of dietary proteins have such effects is not understood. It may possibly be related to the aberrations of lipid metabolism induced by extremely low levels of dietary proteins.