Renal Dysfunction In Rats Research Articles

Indução de resposta inflamatória sistêmica e espessamento de artérias subepicárdicas em um modelo animal de uremia

Although renal dysfunction is a known risk factor for cardiovascular disease (CVD), there are few experimental studies investigating the cardiovascular consequences of this condition. To analyze the impact of the induction of renal dysfunction on biomarkers of cardiovascular risk and on the histology of subepicardial vessels. This experimental study involved thirty Wistar male rats, which were divided into two groups. One (chronic kidney disease - CKD group) underwent renal ablation, and the other (SHAM group) was submitted to kidney manipulation only. Both groups were followed up for eight weeks. During follow-up, serum levels of urea, phosphorus and TNF-α were measured. Heart tissue was processed for histological analysis. The CKD group had increased levels of urea and phosphorus, in comparison with the SHAM group. The levels of TNF-α were increased in the CKD group and undetectable in the SHAM group (p < 0.05). Thickness of the middle layer of the subepicardial vessels of the CKD group was significantly higher than that of the SHAM group (p = 0.011). Induction of renal dysfunction in rats increased the biomarkers of cardiovascular risk and led to a thickening of the subepicardial vessels when compared with normal controls.

Nephroprotective activity of Macrothelypteris oligophlebia rhizomes ethanol extract

Context: Macrothelypteris oligophlebia (Bak.) Ching (Thelypteridaceae) is a Chinese herbal medicine used traditionally for the treatment of diseases such as edema, boils, burns, and roundworms. However, research about the nephroprotective potential of this plant is not available.Objective: Present study was designed to evaluate the protective effect of ethanol extract of M. oligophlebia rhizomes (EMO) on gentamicin (GM)-induced nephrotoxicity.Materials and methods: Rats were intraperitoneal (i.p.) injected with GM (100 mg/kg) to induce nephrotoxicity and simultaneously EMO (250 and 500 mg/kg) was orally given to GM-treated rats for 8 days. Blood urea nitrogen (BUN), serum creatinine (Cr), malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were evaluated in renal tissues. Histopathological analysis was used for evaluation of the renal damage.Results: Administration with GM-induced renal dysfunction in rats. Pre-treatment with EMO (500 mg/kg) significantly decreased the levels of BUN, Cr, MDA and NO (decreased BUN from 12.71 ± 1.28 to 7.19 ± 0.23 mmol/l, Cr from 39.77 ± 5.34 to 19.17 ± 0.90 μmol/l, MDA from 5.60 ± 0.37 to 2.63 ± 0.24 nmol/ml, and NO from 868.17 ± 22.67 to 589.51 ± 8.83 μmol/ml), and also restored the activities of renal antioxidant enzymes (SOD, CAT, and GSH-Px) (restored SOD from 1.59 ± 0.17 to 2.94 ± 0.13 U/mg protein, CAT from 3.22 ± 0.34 to 10.57 ± 0.27 U/mg protein, and GSH-Px from 9.11 ± 1.29 to 20.72 ± 1.83 U/mg protein).Discussion and conclusion: Our results suggest that the rhizomes of M. oligophlebia potentially have a protective role in renal tissue against oxidative stress in acute renal failure.

Montelukast ameliorates kidney function and urinary bladder sensitivity in experimentally induced renal dysfunction in rats

Effect of montelukast on the renal dysfunction induced by cisplatin was investigated. A single dose of cisplatin (7 mg/kg, i.p.) induced nephrotoxicity, which was manifested by increasing the sensitivity of isolated urinary bladder rings to acetylcholine (ACh) together with a significant elevation of serum creatinine, blood urea nitrogen, and lactate dehydrogenase. On the other hand, serum albumin was significantly decreased. Moreover, renal dysfunction was further confirmed by a significant increase in lipid peroxides that were measured as malondialdehyde (MDA) in kidney tissue homogenate. Kidney reduced glutathione (GSH) content and superoxide dismutase (SOD) activity were measured, which were decreased and increased, respectively. Administration of montelukast (10 mg/kg/day, p.o.) 5 days before and 5 days after cisplatin injection significantly ameliorated the renotoxic effects of cisplatin, as judged by a significant reduction in the responses of isolated bladder rings to ACh. The deleterious changes induced by cisplatin treatment in kidney function parameters and oxidative stress markers were significantly mitigated by montelukast treatment. Montelukast may be a beneficial remedy for cisplatin-induced renal dysfunction.

Caffeic acid phenethyl ester protects against oxidative stress‐related renal dysfunction in rats treated with cyclosporin A

The therapeutic index of cyclosporin A (CsA), an immunosuppressive drug, is limited by its nephrotoxic effect. Oxidative stress is suggested to play a crucial role as pathogenic factors. The present study aimed at investigating the effects of caffeic acid phenethyl ester (CAPE), a phenolic antioxidant, on renal function, morphology, and oxidative stress following CsA treatment. Rats were treated with vehicle, CsA (50 mg/kg), and CsA plus CAPE (10 and 30 μmol/kg) for 10 days. Renal function, histopathology, and tissue malondialdehyde (MDA) and reduced glutathione (GSH) levels were evaluated 24 h after the last treatment. CsA produced nephrotoxicity as indicated by a significant increase in serum creatinine and blood urea nitrogen, but decrease creatinine and urea clearance compared to those treated with vehicle. Severe vacuolations and tubular necrosis were evident in the kidney of CsA-treated rats. CsA also increased renal MDA and decreased GSH content significantly. Administration of CAPE along with CsA restored all the changes caused by CsA. These results clearly demonstrate the pivotal role of oxidative stress and its relation to renal dysfunction and also point to the protective potential of CAPE against CsA nephrotoxicity. The protection afforded by CAPE is mediated, at least in part, through inhibiting renal lipid peroxidation and enhancing or maintaining the antioxidant glutathione content.

Diazinon-induced oxidative stress and renal dysfunction in rats

Diazinon ( O, O-diethyl- O-[2-isopropyl-6-methyl-4-pyrimidinyl] phosphoro thioate), an organo-phosphate insecticide, has been used worldwide in agriculture and domestic for several years, which has led to a variety of negative effects in non target species including humans. However, its nephrotoxic effects and mechanism of action has not been fully elucidated so far. Therefore, the present study was aimed at evaluating the nephrotoxic effects of diazinon and its mechanism of action with special reference to its possible ROS generating potential in rats. Treatment of rats with diazinon significantly enhances renal lipid peroxidation which is accompanied by a decrease in the activities of renal antioxidant enzymes (e.g. catalase, glutathione peroxidise, glutathione reductase, glucose-6-phosphate dehydrogenase, glutathione S-transferase) and depletion in the level of glutathione reduced. In contrast, the activities of renal γ-glutamyl transpeptidase and quinone reductase were increased. Parallel to these changes, diazinon treatment enhances renal damage as evidenced by sharp increase in blood urea nitrogen and serum creatinine. Additionally, the impairment of renal function corresponds histopathologically. In summary, our results indicate that diazinon treatment eventuates in decreased renal glutathione reduced, a fall in the activities of antioxidant enzymes including the enzymes involved in glutathione metabolism and excessive production of oxidants with concomitant renal damage, all of which are involved in the cascade of events leading to diazinon-mediated renal oxidative stress and toxicity. We concluded that in diazinon exposure, depletion of antioxidant enzymes is accompanied by induction of oxidative stress that might be beneficial in monitoring diazinon toxicity.

Sida rhomboidea.Roxb leaf extract ameliorates gentamicin induced nephrotoxicity and renal dysfunction in rats

Sida rhomboidea.Roxb (SR) known as "Mahabala" in Ayurveda and marketed as "Shahadeyi" is used in ethnomedicine to treat ailments such as dysuria and urinary disorders. To evaluate nephroprotective potential of SR against gentamicin (GM) induced nephrotoxicity and renal dysfunction. Nephrotoxicity was induced in rats with GM (100 mg/kg bodyweight (i.p.) for 8 days) and were treated with SR extract (200 and 400 mg/kg bodyweight (p.o.) for 8 days) or 0.5% carboxymethyl cellulose (vehicle). Plasma and urine urea and creatinine, renal enzymatic and non-enzymatic antioxidants along with lipid peroxidation were evaluated in various experimental groups. GM treatment induced significant elevation (p<0.05) in plasma and urine urea, creatinine, renal lipid peroxidation along with significant decrement (p<0.05) in renal enzymatic and non-enzymatic antioxidants. SR treatment to GM treated rats (GM+SR) recorded significant decrement (p<0.05) in plasma and urine urea and creatinine, renal lipid peroxidation along with significant increment (p<0.05) in renal enzymatic and non-enzymatic antioxidants. SR leaf extract ameliorates GM induced nephrotoxicity and renal dysfunction and thus validates its ethnomedicinal use.

Allopurinol, rutin, and quercetin attenuate hyperuricemia and renal dysfunction in rats induced by fructose intake: renal organic ion transporter involvement

Fructose consumption has been recently related to an epidemic of metabolic syndrome, and hyperuricemia plays a pathogenic role in fructose-induced metabolic syndrome. Fructose-fed rats showed hyperuricemia and renal dysfunction with reductions of the urinary uric acid/creatinine ratio and fractional excretion of uric acid (FE(ur)), as well as other features of metabolic syndrome. Lowering serum uric acid levels with allopurinol, rutin, and quercetin increased the urinary uric acid/creatinine ratio and FE(ur) and attenuated other fructose-induced metabolic abnormalities in rats, demonstrating that hyperuricemia contributed to the deficiency of renal uric acid excretion in this model. Furthermore, we found that fructose upregulated the expression levels of rSLC2A9v2 and renal-specific transporter (rRST), downregulated the expression levels of organic anion transporters (rOAT1 and rUAT) and organic cation transporters (rOCT1 and rOCT2), with the regulators prostaglandin E(2) (PGE(2)) elevation and nitric oxide (NO) reduction in rat kidney. Allopurinol, rutin, and quercetin reversed dysregulations of these transporters with PGE(2) reduction and NO elevation in the kidney of fructose-fed rats. These results suggested that dysregulations of renal rSLC2A9v2, rRST, rOAT1, rUAT, rOCT1, and rOCT2 contributed to fructose-induced hyperuricemia and renal dysfunction. Therefore, these renal transporters may represent novel therapeutic targets for the treatment of hyperuricemia and renal dysfunction in fructose-induced metabolic syndrome.

Renal ischemia/reperfusion injury in rats is attenuated by a synthetic glycine derivative

Renal ischemia/reperfusion is a common cause of acute renal failure. Glycine is an effective anti-inflammatory, cytoprotective agent and is reported to have a beneficial effect against ischemia/reperfusion injury in various organs. Previous research notes that free radicals and inflammatory leukocytes both play important roles in the pathogenesis of renal ischemia/reperfusion injury. To develop new therapeutic agents against renal ischemia/reperfusion injury, we sought to link an antioxidant moiety (nitronyl nitroxide) to glycine in the hope that the resulting glycine-nitronyl nitroxide conjugate (GNN) would provide a synergetic protection against renal ischemia/reperfusion injury. In this manuscript, we report the synthesis and biological evaluation of the GNN conjugate. The biological activity of the GNN conjugate was evaluated in an in vivo rat model of renal ischemia/reperfusion induced injury and oxidative change. Since the GNN conjugate markedly reduced elevated levels of tissue lipid peroxidation and attenuated renal dysfunction in rats subjected to renal ischemia/reperfusion, it might be possible to develop the GNN conjugate into a potential therapeutic agent against renal ischemia/reperfusion injury.

Naringenin protects against cadmium-induced oxidative renal dysfunction in rats

Cadmium (Cd) is an environmental and industrial pollutant that affects various organs in human and experimental animals. Naringenin is a naturally occurring plant bioflavonoid found in citrus fruits, which has been reported to have a wide range of pharmacological properties. A body of evidence has accumulated implicating the free radical generation with subsequent oxidative stress in the biochemical and molecular mechanisms of cadmium toxicity. Since kidney is the critical target organ of chronic Cd toxicity, we carried out this study to investigate the effects of naringenin on Cd-induced toxicity in the kidney of rats. In experimental rats, oral administration of cadmium chloride (5 mg/(kg day)) for 4 weeks significantly induced the renal damage which was evident from the increased levels of serum urea, uric acid, creatinine with a significant ( p < 0.05) decrease in creatinine clearance. Cadmium also significantly decreased the levels of urea, uric acid and creatinine in urine. A markedly increased levels of lipid peroxidation markers (thiobarbituric acid reactive substances and lipid hydroperoxides) and protein carbonyl contents with significant ( p < 0.05) decrease in non-enzymatic antioxidants (total sulfhydryl groups, reduced glutathione, vitamin C and vitamin E) and enzymatic antioxidants (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione S-transferase (GST)) as well as glutathione metabolizing enzymes (glutathione reductase (GR) and glutathione-6-phosphate dehydrogenase (G6PD)) were also observed in cadmium-treated rats. Co-administration of naringenin (25 and 50 mg/(kg day)) along with Cd resulted in a reversal of Cd-induced biochemical changes in kidney accompanied by a significant decrease in lipid peroxidation and an increase in the level of renal antioxidant defense system. The histopathological studies in the kidney of rats also showed that naringenin (50 mg/(kg day)) markedly reduced the toxicity of Cd and preserved the normal histological architecture of the renal tissue. The present study suggest that the nephroprotective potential of naringenin in Cd toxicity might be due to its antioxidant and metal chelating properties, which could be useful for achieving optimum effects in Cd-induced renal damage.

NMDA receptor blocker ameliorates ischemia-reperfusion-induced renal dysfunction in rat kidneys

N-methyl-d-aspartate (NMDA) receptor activated by glutamate/glycine is located in the kidneys. The NMDA receptor subunit NR1 is increased in damaged renal tissue. This study explored the role of NMDA receptors in ischemia-reperfusion-induced renal dysfunction in rats. With Western blot analysis and renal functional assay, NMDA receptor expression was evaluated, as well as its functional role in female Wistar rat kidneys after 45 min of unilateral ischemia followed by 24 h of reperfusion. The effects of intrarenal NMDA receptor agonist and antagonist on renal blood flow (RBF), glomerular filtration rate (GFR), urine volume (UV), sodium (U(Na)V), and potassium (U(K)V) excretion were determined. NMDA NR1 was present in the glomeruli, brush-border membrane, and outer medulla but not in the cortex and inner medulla. Homogenous distribution of non-NMDA GluR2/3, sparse kainate KA1, and undetectable group I of metabotropic glutamate receptor were noted in the control kidneys. Ischemia-reperfusion kidneys showed enhanced renal NR1, but not NR2C and GluR2/3 expression, and were associated with decreased GFR/RBF and natriuretic/diuretic responses. Intrarenal NMDA agonists significantly reduced GFR, UV, U(Na)V, and U(K)V but had no effect on blood pressure and RBF in sham control and ischemia-reperfusion kidneys. NMDA antagonist d-2-amino-5-phosphonopentanoic acid (D-AP-5) treatment completely abolished NMDA-induced renal dysfunction. D-AP-5 treatment significantly ameliorated ischemia-reperfusion-induced glomerular and tubular dysfunction by restoring decreased GFR, UV, and U(Na)V levels. Ischemia-reperfusion upregulates renal NMDA NR1 receptor expression, leading to reduced glomerular and tubular function in the kidneys. The NMDA antagonist can ameliorate ischemia-reperfusion-induced renal dysfunction.

Effects of α-lipoic acid on ischemia-reperfusion-induced renal dysfunction in rats

We investigated whether alpha-lipoic acid (alpha-LA), an antioxidant, attenuates the ischemia-reperfusion (I/R)-induced dysregulation of these transporters. Both renal pedicles of male Sprague-Dawley rats were clamped for 40 min. alpha-LA (80 mg/kg) was administered intraperitoneally before and immediately after induction of ischemia. After 2 days, the expression of aquaporins (AQPs), sodium transporters, and nitric oxide synthases (NOS) was determined in the kidney by immunoblotting and immunohistochemistry. The expression of endothelin-1 (ET-1) mRNA was determined by real-time PCR. Activities of adenylyl cyclase and guanylyl cyclase were measured by stimulated generation of cAMP and cGMP, respectively. The expression of AQP1-3 as well as that of the alpha(1)-subunit of Na-K-ATPase, type 3 Na/H exchanger, Na-K-2Cl cotransporter, and Na-Cl cotransporter was markedly decreased in response to I/R. The expression of type VI adenylyl cyclase was decreased in I/R-injured rats, which was counteracted by the treatment of alpha-LA. AVP-stimulated cAMP generation was blunted in I/R rats and was then ameliorated by alpha-LA treatment. alpha-LA treatment attenuated the downregulation of AQPs and sodium transporters. The expression of endothelial NOS was decreased in I/R rats, which was prevented by alpha-LA. The cGMP generation in response to sodium nitroprusside was blunted in I/R rats, which was also significantly prevented by alpha-LA. The mRNA expression of ET-1 was increased, which was recovered to the control level by alpha-LA treatment. In conclusion, alpha-LA treatment prevents I/R-induced dysregulation of AQPs and sodium transporters in the kidney, possibly through preserving normal activities of local AVP/cAMP, nitric oxide/cGMP, and ET systems.

Effects of mycophenolate mofetil on cisplatin-induced renal dysfunction in rats

Inflammation and oxidative stress are important events among the plethora of mechanisms involved in cisplatin (CDDP)-induced nephrotoxicity. The aim of this study was to evaluate the effect of mycophenolate mofetil (MMF), an immunosuppressive, in the protection against CDDP-induced renal dysfunction. Rats were divided into four groups; untreated-control group, CDDP-treated group (7 mg/kg, single intraperitoneal dose), MMF-treated group (40 mg/kg/day orally for 5 successive days) and the fourth group was treated with both drugs and MMF treatment was started 1 day prior to CDDP administration. Nephrotoxicity was assessed 7 days after the CDDP treatment by measuring serum indices of nephrotoxicity, kidney weight as a percentage of total body weight, kidney's tissue peroxidative alterations and total nitrate/nitrite concentration (NOx) and the results were confirmed histopathologically. Rats treated with CDDP showed marked nephrotoxicity as evidenced from the significant increase in serum creatinine and urea levels and decrease in serum calcium and albumin levels. Kidneys of CDDP-treated rats showed significant increases in kidney weight and malondialdehyde (MDA) production level and decreases in total NOx concentration, glutathione peroxidase (GPx) activity and reduced glutathione (GSH) content levels. Histopathological assessment of kidneys of CDDP-treated rats revealed extensive tubular necrosis with "sloughing off" of the renal tubular lining cells, intratubular hyaline casts and mononuclear cell infiltration. Treatment with MMF significantly protected the rats against CDDP-induced nephrotoxicity. The rise in serum creatinine and urea levels, kidney weight and kidney tissue MDA production, depletion of "endogenous antioxidant reserve" including GPx activity and reduced GSH content levels and the deleterious histopathological changes induced by CDDP treatment were significantly mitigated by MMF treatment. MMF treatment dramatically ameliorates CDDP-induced renal dysfunction.

Gene expression profiling of renal dysfunction in rats with experimental cirrhosis

Renal dysfunction is a frequent complication in advanced cirrhosis. The mechanisms underlying this complication have classically been addressed through conventional methods of study of candidate genes, but never on a genome-wide scale. In this investigation, we used microarrays to monitor global gene expression changes in the kidney of cirrhotic rats. Renal samples were obtained from control and carbon tetrachloride-induced cirrhotic rats. RNA samples were reverse-transcribed into Cy5-labeled cDNA, combined with a Cy3-labeled reference and hybridized to oligonucleotide microarrays. Microarrays were scanned in a Genepix 4000B and data analyzed by Luminator v2.0 software. A total of 620 genes were differentially regulated (354 up and 266 down) in the cirrhotic kidney, accounting for approximately 11% of all analyzed transcripts. Functional grouping of these genes revealed that 47 were related to the category of vascular tone and 85 to transporters/channels. Among these, we identified genes and pathways already associated with renal dysfunction as well as a new subset of genes previously unknown to participate in this complication, including a G protein-coupled receptor that binds apelin, a protein phosphatase (calcineurin B) and a number of neuropeptide receptors and growth factors. These findings furnish new data for mechanistic investigation into renal dysfunction in cirrhosis.

Effect of Spirulina, a blue green algae, on gentamicin‐induced oxidative stress and renal dysfunction in rats

Gentamicin (GM), an aminoglycoside, is widely employed in clinical practice for the treatment of serious Gram-negative infections. The clinical utility of GM is limited by the frequent incidence of acute renal failure. Experimental evidences suggest that oxidative and nitrosative stress play an important role in GM nephrotoxicity. Spirulina fusiformis is a blue green algae with potent free radical scavenging properties. The present study was designed to investigate renoprotective potential of S. fusiformis, against GM-induced oxidative stress and renal dysfunction. Spirulina fusiformis (500, 1000, 1500 mg/kg, p.o.) was administered 2 days before and 8 days concurrently with GM (100 mg/kg, i.p.). Renal injury was assessed by measuring serum creatinine, blood urea nitrogen and creatinine clearance and serum nitrite levels. Renal oxidative stress was determined by renal malondialdehyde levels, reduced glutathione levels and by enzymatic activity of superoxide dismutase (SOD) and catalase. Chronic GM administration resulted in marked renal oxidative and nitrosative stress and significantly deranged renal functions. Treatment with S. fusiformis significantly and dose-dependently restored renal functions, reduced lipid peroxidation and enhanced reduced glutathione levels, SOD and catalase activities. The results of present study clearly demonstrate the pivotal role of reactive oxygen species and their relation to renal dysfunction and point to the therapeutic potential of S. fusiformis in GM-induced nephrotoxicity.

6‐Gingerol prevents cisplatin‐induced acute renal failure in rats

Nephrotoxicity is a major complication and a dose limiting factor for cisplatin therapy. Recent evidence suggests that enhanced oxidative stress caused by oxygen-centered free radicals may contribute to the pathogenesis of cisplatin-induced acute renal failure. 6-Gingerol is claimed to be a potent antioxidant. The present study was performed to explore the renoprotective potential of 6-gingerol on cisplatin-induced oxidative stress and renal dysfunction. 6-Gingerol in dosages of 12.5, 25, 50 mg/kg was administered 2 days before and 3 days after cisplatin administration. Renal injury was assessed by measuring serum creatinine, blood urea nitrogen, creatinine, urea clearance and serum nitrite levels. Renal oxidative stress was assessed by determining renal malondialdehyde levels, reduced glutathione levels and enzymatic activities of superoxide dismutase and catalase. A single dose of cisplatin resulted in marked renal oxidative and nitrosative stress and significantly deranged renal functions. 6-Gingerol treatment significantly and dose-dependently restored renal functions, reduced lipid peroxidation and enhanced the levels of reduced glutathione and activities of superoxide dismutase and catalase. The present study demonstrates the renoprotective potential of 6-gingerol against cisplatin-induced oxidative stress and renal dysfunction in rats. Hence, 6-gingerol has a potential to be used as therapeutic adjuvant in cisplatin nephrotoxicity.

MYOCARDIAL ISCHEMIA/REPERFUSION-INDUCED OXIDATIVE RENAL DAMAGE IN RATS: PROTECTION BY CAFFEIC ACID PHENETHYL ESTER (CAPE)

Myocardial ischemia-reperfusion (MI/R) may induce renal damage. A rat model of M/IR injury was established. The left coronary artery was clamped for 30 min, constituting the ischemic period, and was then released for 120 min, thus constituting the reperfusion period. The purpose of this study was to evaluate the effects of caffeic acid phenethyl ester (CAPE), an antioxidant, on renal dysfunction in rats undergoing MI/R. CAPE (50 mumol/kg) was administered by infusion 10 min before ischemia and during occlusion. Hemodynamic changes were recorded during the different periods. At the end of the reperfusion period, rats were sacrificed, and the kidneys were quickly removed for biochemical determination and histopathological analysis. MI/R was accompanied by a significant increase in malondialdehyde (MDA) production and decrease in glutathione (GSH) content in the rat kidney. Administration of CAPE reduced MDA production and prevented depletion of GSH content. These beneficial changes in these biochemical parameters were also associated with parallel changes in histopathological appearance. These findings imply that MI/R plays a causal role in kidney injury through overproduction of oxygen radicals or insufficient antioxidant, and CAPE exerts renal-protective effects probably by its radical scavenging and antioxidant activities.

Green tea extract attenuates cyclosporine A-induced oxidative stress in rats

Cyclosporine A (CsA) nephrotoxicity underweighs the therapeutic benefits of such a powerful immunosuppressant. Whether oxidative stress plays a role in such toxicity is not well delineated. We investigated the potential of green tea extract (GTE) to attenuate CsA-induced renal dysfunction in rats. Three main groups of Sprague–Dawley rats were used: CsA, GTE, and GTE plus CsA-receiving animals. Corresponding control groups were also used. CsA was administered in a dose of 20 mg kg −1 day −1, i.p., for 21 days. In the GTE/CsA groups, the rats received different concentrations of GTE (0.5, 1.0 and 1.5%), as their sole source of drinking water, 4 days before and 21 days concurrently with CsA. The GTE group was treated with 1.5% concentration of GTE only for 25 days. A concomitant administration of GTE, to CsA receiving rats, markedly prevented the generation of thiobarbituric acid-reacting substances (TBARS) and significantly attenuated CsA-induced renal dysfunction as assessed by estimating serum creatinine, blood urea nitrogen, uric acid and urinary excretion of glucose. A considerable improvement in terms of reduced glutathione content and activity of antioxidant enzymes in the kidney homogenate of the GTE/CsA-receiving rats was observed. The activity of lysosomal enzymes, N-acetyl-β-glucosaminidase, β-glucuronidase and acid phosphatase was significantly inhibited following GTE co-administration. Our data prove the role of oxidative stress in the pathogenesis of CsA-induced kidney dysfunction. Supplementation of GTE could be useful in reducing CsA nephrotoxicity in rats. However, clinical studies are warranted to investigate such an effect in human subjects.

Protection by ozone preconditioning is mediated by the antioxidant system in cisplatin-induced nephrotoxicity in rats.

BACKGROUND: Acute renal failure is a dose-limiting factor of cisplatin chemotherapy. Here, we show the protective effect of ozone oxidative preconditioning against cisplatin-induced renal dysfunction in rats. Ozone oxidative preconditioning is a prophylactic approach, which favors the antioxidant-pro-oxidant balance for preservation of the cell redox state by increasing antioxidant endogenous systems in various in vivo and in vitro experimental models. AIMS: To analyze the protective role of ozone oxidative preconditioning against cisplatin-induced nephrotoxicity. METHODS: Male Sprague-Dawley rats were pretreated with 15 intrarectal applications of ozone/oxygen mixture at 0.36, 0.72, 1.1, 1.8 and 2.5 mg/kg before cisplatin intraperitoneal injection (6 mg/kg). Serum and kidneys were extracted and analyzed 5 days after cisplatin treatment for determinations of the renal content of glutathione, thiobarbituric acid-reactive substances, renal concentration and enzymatic activities of catalase, superoxide dismutase and glutathione peroxidase. RESULTS: Ozone pretreatment prevented the increase in serum creatinine levels, the glutathione depletion and the inhibition of superoxide dismutase, catalase and glutathione peroxidase activities induced by cisplatin in the rat kidney. Also, the renal content of thiobarbituric acid-reactive substances was decreased by ozone therapy. These protective effects of ozone were dose dependent. CONCLUSIONS: Intrarectal ozone therapy prevented effectively the renal antioxidant unbalance induced by cisplatin treatment.

L-arginine ameliorates kidney function and urinary bladder sensitivity in experimentally-induced renal dysfunction in rats.

Effects of L-arginine and NG-nitro-L-arginine methyl ester (L-NAME) on the renal dysfunction that is induced by cisplatin (CDDP) were investigated. A single dose of CDDP (7.5 mg/kg i.p.) induced renotoxicity, which was manifested by increasing the sensitivity of isolated urinary bladder rings to acetylcholine (ACh), together with a significant elevation of serum urea and creatinine, and a severe decrease in serum albumin. Moreover, renal dysfunction was further confirmed by a significant decrease of enzyme activities, such as glutathione peroxidase, GSH-Px (E.C 1.11.1.9), catalase (E.C 1.11.1.6), as well as a significant increase in lipid peroxides that were measured as malondialdhyde (MDA) in kidney tissue homogenates. The administration of L-arginine (70 mg/kg/d p.o in drinking water 5 d before and 5 d after the CDDP injection) significantly ameliorated the renotoxic effects of CDDP, as judged by restoring the normal responses of isolated bladder rings to Ach, and also by an improvement in a range of renal function indices, which included serum urea and creatinine concentrations and kidney weight. In addition, L-arginine prevents the rise of MDA, as well as a reduction of GSH-Px and catalase activities in kidney tissues homogenates. On the other hand, the administration of L-NAME (4 mg/kg/d p.o) resulted in no protection against renal dysfunction that was induced by CDDP treatment. The findings of this study suggest that L-arginine can attenuate kidney injury that is produced by CDDP treatment. In addition, L-arginine may be a beneficial remedy for CDDP-induced renal toxicity, and could be used to improve the therapeutic index of CDDP.

Effect of U-74500A, A 21-Aminosteroid on Renal Ischemia-Reperfusion Injury in Rats

Renal ischemia-reperfusion injury constitutes the most common pathogenic factor for acute renal failure and is the main contributor to renal dysfunction in allograft recipients and revascularization surgeries. Many studies have demonstrated that reactive oxygen species play an important role in ischemic acute renal failure. The aim of the present study was to investigate the effects of the synthetic antioxidant U-74500A, a 21-aminosteroid in a rat model of renal ischemia-reperfusion injury. Renal ischemia-reperfusion was induced by clamping unilateral renal artery for 45 min followed by 24 h of reperfusion. Two doses of U-74500A (4.0 mg/kg, i.v.) were administered 45 min prior to renal artery occlusion and then 15 min prior to reperfusion. Tissue lipid peroxidation was measured as thiobarbituric acid reacting substances (TBARS) in kidney homogenates. Renal function was assessed by estimating serum creatinine, blood urea nitrogen (BUN), creatinine and urea clearance. Renal morphological alterations were assessed by histopathological examination of hematoxylin-eosin stained sections of the kidneys. Ischemia-reperfusion produced elevated levels of TBARS and deteriorated the renal function as assessed by increased serum creatinine, BUN and decreased creatinine and urea clearance as compared to sham operated rats. The ischemic kidneys of rats showed severe hyaline casts, epithelial swelling, proteinaceous debris, tubular necrosis, medullary congestion and hemorrhage. U-74500A markedly attenuated elevated levels of TBARS as well as morphological changes, but did not improve renal dysfunction in rats subjected to renal ischemia-reperfusion. These results clearly demonstrate the in vivo antioxidant effect of U-74500A, a 21-aminosteroid in attenuating renal ischemia-reperfusion injury.