Rutin attenuates gentamicin-induced renal damage by reducing oxidative stress,inflammation, apoptosis,and autophagy in rats

Abstract

Gentamicin is commonly used against gram-negative microorganisms. Its therapeutic use is mainly limited by nephrotoxicity. This study was aimed at evaluating the effect of rutin on oxidative stress, inflammation, apoptosis, and autophagy in gentamicin-induced nephrotoxicity in rats. The rats were treated with saline intraperitoneally (group I), 150?mg/kg of rutin orally (group II), 80?mg/kg of gentamicin intraperitoneally for 8?d (group III), or 150?mg/kg of rutin plus 80?mg/kg of gentamicin (group IV). The serum urea, creatinine, kidney malondialdehyde (MDA), and reduced glutathione (GSH) levels and superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activity and protein concentration were measured, and renal histopathology analysis and immunohistochemical staining were performed. Rutin pretreatment attenuated nephrotoxicity induced by gentamicin by reducing the urea, creatinine, and MDA levels and increasing the SOD, CAT, and GPx activity, and the GSH levels. The rutin also inhibited inducible nitric oxide synthase (iNOS), cleaved caspase-3 and light chain 3B (LC3B), as evidenced by immunohistochemical staining. The present study demonstrates that rutin exhibits antioxidant, anti-inflammatory, anti-apoptotic, and anti-autophagic effects and that it attenuates gentamicin-induced nephrotoxicity in rats.     

Melatonin, a pineal hormone with antioxidant property, protects against gentamicin-induced nephrotoxicity in rats

The present study investigated the effects of melatonin, an antioxidant, on gentamicin-induced nephrotoxicity in rats. Melatonin (5 mg/kg p.o.) was used 3 days before and 8 days simultaneously with gentamicin (80 mg/kg i.p.) Saline-treated animals served as controls. Determinations of urinary creatinine, N-acetyl-beta-D-glucosaminidase, glucose, protein, blood urea, serum creatinine, plasma and kidney tissue malondialdehyde (MDA), and antioxidant enzyme levels in kidney tissue were done after 8 days of gentamicin treatment. The kidneys were also examined for morphological changes using histological techniques. Gentamicin caused nephrotoxicity as evidenced by marked elevation in blood urea and serum creatinine. Mean blood urea and serum creatinine levels were 289+/-50, and 2.5+/-0.5 mg/dl, respectively, in rats treated with gentamicin. Melatonin significantly protected the rats from gentamicin-induced nephrotoxicity; blood urea and serum creatinine levels were 23+/-2.7 and 0.88+/-0.19 mg/dl, respectively. The creatinine clearance was decreased with gentamicin treatment (0.048+/- 0.007 ml/min) as compared with controls (0.41+/-0.08 ml/h/kg). In rats treated with melatonin plus gentamicin, the creatinine clearance was similar to controls (0.41+/-0.08 ml/h/kg). The product of lipid peroxidation (MDA) was markedly increased in plasma (2.10+/-0.15 nmol) and kidney tissue (8.87+/-3.2 nmol/mg protein) with gentamicin treatment. Melatonin prevented the gentamicin-induced rise in plasma MDA (1.03+/-0.27 nmol) and kidney tissue MDA (2.57+/-0.87 nmol/mg protein). An increased excretion of urinary N-acetyl-beta-D-glucosaminidase, glucose, and protein by gentamicin was also prevented by melatonin. Kidneys from gentamicin-treated rats showed tubular epithelial loss with intense granular degeneration involving more than 50% of renal cortex, while there were findings comparable to controls in melatonin plus gentamicin treated rats. The present study indicates that melatonin significantly protects against gentamicin-induced renal toxicity in Wistar rats.     

Tissue kallikrein attenuates salt-induced renal fibrosis by inhibition of oxidative stress

BACKGROUND: High salt intake induces hypertension, cardiac hypertrophy, and progressive renal damage. Progressive renal injury is the consequence of a process of destructive fibrosis. Using gene transfer approach, we have shown that the tissue kallikrein-kinin system (KKS) plays an important role in protection against renal injury in several hypertensive rat models. In this study, we further investigated the effect and potential mechanisms mediated by kallikrein on salt-induced renal fibrosis. METHODS: Adenovirus harboring the human tissue kallikrein gene was delivered intravenously into Dahl salt-sensitive (DSS) rats on a high salt diet for 4 weeks. Two weeks after gene delivery, the effect of kallikrein on renal fibrosis was examined by biochemical and histologic analysis. RESULTS: Kallikrein gene delivery resulted in reduced blood urea nitrogen (BUN), urinary protein and albumin levels in DSS rats on a high salt diet. Expression of recombinant human tissue kallikrein was detected in the sera and urine of rats injected with the kallikrein gene. Histologic investigation showed that kallikrein gene delivery significantly reduced glomerular and tubular fibrosis scores and collagen deposition, as well as renal cell proliferation, compared to rats on a high salt diet injected with control virus. Kallikrein gene transfer significantly increased nitric oxide and cyclic guanosine monophosphate (cGMP) levels in conjunction with reduced salt-induced nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADPH) oxidase activity, superoxide production, transforming growth factor-beta1 (TGF-beta1) mRNA and protein levels, and TGF-beta1 immunostaining. CONCLUSION: These results indicate that tissue kallikrein protects against renal fibrosis in hypertensive DSS rats through increased nitric oxide bioavailability and suppression of oxidative stress and TGF-beta expression.     

Prostacyclin protects renal tubular cells from gentamicin-induced apoptosis via a PPARalpha-dependent pathway

To study the protective effect of prostacyclin (PGI2) we increased PGI2 production by infected NRK-52E cells with an adenovirus carrying cyclooxygenase-1 and prostacyclin synthase. PGI2 overexpression protected these cells from gentamicin-induced apoptosis by reducing cleaved caspase-3 and caspase-9, cytochrome c, and decreasing generation of reactive oxygen species. Expression of the nuclear receptor of PGI2, peroxisome proliferator-activated receptor-alpha (PPARalpha), was reduced during gentamicin treatment of the cells, while its overexpression significantly inhibited gentamicin-induced apoptosis and the amount of cleaved caspase-3. Transformation with PPARalpha short interfering RNA abolished the protective effect of PGI2 overproduction in gentamicin-treated cells. The PPARalpha activator docosahexaenoic acid given to gentamicin-treated mice significantly reduced the number of apoptotic cells in renal cortex, but this protective effect was not seen in PPARalpha knockout mice. Our study suggests that increased endogenous PGI2 production protects renal tubular cells from gentamicin-induced apoptosis through a PPARalpha-signaling pathway.     

Protective effect of KCl loading in gentamicin nephrotoxicity

Aminoglycoside nephrotoxicity in experimental animals can be reduced by calcium loading, inducing diabetes, and giving thyroid hormone, while a potassium deficient diet enhances aminoglycoside nephrotoxicity. This study investigated whether potassium loading protects against gentamicin nephrotoxicity in the rat. In part I, group GK ate a diet containing 3.5% potassium and drank 0.2 mol/L KCl. Pair-fed rats eating a standard diet, group G, ate a 1% potassium diet and drank water. After 10 days, each group received gentamicin subcutaneously, 60 mg/kg twice daily for 8 days. The control groups, K and C, received the high or normal potassium diet, respectively. To control for a protective effect from a high solute load, the effect of equimolar NaCl loading was studied in group GNa and Na. At the end of the 8 days of gentamicin, inulin clearance was significantly higher in GK compared with G(0.6 +/- 0.1 v 0.3 +/- 0.1 mL/min per 100 g body weight [BW], P less than 0.05), but group GNa (0.4 +/- 0.1 mL/min per 100 g BW) was not different from group G. Morphological studies demonstrated that potassium-loaded rats (group GK) had significantly less proximal tubular necrosis compared with rats on a standard potassium diet, group G. Sodium loading did not protect against cellular necrosis. Part II studied renal function, cortical Na,K-adenosine triphosphatase (ATPase) and gentamicin accumulation after 2 days of gentamicin to determine the early functional and biochemical effects of potassium loading before overt renal functional impairment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Rosiglitazone,peroxisome proliferator receptor-gamma agonist,ameliorates gentamicin-induced nephrotoxicity in rats

Nephrotoxicity is a major complication of gentamicin (GEN), which is widely used in the treatment of severe gram-negative infections. Reactive oxygen spaces (ROS) are important mediators of gentamicin-induced nephrotoxicity. Peroxisome proliferator-activated receptors (PPARs) have different activities including antioxidant properties. This study was performed to investigate the protective role of PPAR-γ agonist against GEN-induced nephrotoxicity. Male Wistar Albino rats were randomly divided into the following four groups, each of which consisted of six animals: (1) control; (2) intraperitoneally injected with GEN for 14 consecutive days (100 mg/kg/day); (3) treatment with rosiglitazone (RSG) via nasogastric gavage (10 mg/kg/daily for 14 days); (4) treatment with GEN + RSG combination for 14 day. Rats were decapitated on the 15th day and kidneys were removed. Urine was collected for every 24 h for the determination of daily urine volume. Urea, creatinine, Na⁺ and K⁺ levels were measured in blood. Malondialdehyde (MDA), reduced glutathion (GSH), and nitric oxide (NO) levels along with glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD) activities were determined in the renal tissue. Changes in body weight were recorded. GEN treatment was found to cause nephrotoxicity as evidenced by elevation of serum urea and creatinine levels. Renal impairment was also assessed by the renal histology. The significant decrease in GSH and increases in MDA and NO levels as well as a decrease in GSH-Px, CAT, and SOD activities indicated that GEN-induced renal damage was mediated through oxidative reactions. On the other hand, RSG administration protected kidney tissue against GEN-induced and free radical-mediated oxidative renal damage in rats.     

Simvastatin ameliorates gentamicin-induced renal injury in rats

Gentamicin nephrotoxicity is one of the most common causes of acute renal failure. Simvastatin is one of the antioxidative drugs, which has anti-inflammatory and anabolic effects and modulates the immune system. The present study was conducted to assess the effect of simvastatin on ameliorating the gentamicin-induced renal injury in 87 Sprague-Dawley rats, which were allocated randomly to 11 study groups: (A) and (B) groups with only gentamicin in 2 dosages; (C), (D), and (E) gentamicin 50 mg/kg/day and simvastatin with different dosage; (F), (G), and (H) gentamicin 80 mg/kg/day and simvastatin with different dosage; (I) only simvastatin; (J) Injected normal saline; (K) control (no gentamicin and no simvastatin) group. Our study intervention period for injection of drugs was 12 days. Serum creatinine level and clearance were measured in all groups. At the end of the study, the rats were killed and both kidneys were removed and processed for histopathologic examination using the standard methods. The 50 mg/kg/day dose was utilized because it induces a mild form of renal toxicity, whereas the 80 mg/kg/day dose cause a more severe degree of renal injury. Morphologic examination of specimens from all rats was qualitatively assessed with blindness to treatment groups and proximal tubular profiles that were presented in each file were counted. The results demonstrated amelioration of gentamicin-induced renal toxicity in rats by simvastatin due to its antioxidant drug dose-related effect.     

Kallikrein gene delivery improves serum glucose and lipid profiles and cardiac function in streptozotocin-induced diabetic rats

We investigated the role of the kallikrein-kinin system in cardiac function and glucose utilization in the streptozotocin (STZ)-induced diabetic rat model using a gene transfer approach. Adenovirus harboring the human tissue kallikrein gene was administered to rats by intravenous injection at 1 week after STZ treatment. Human kallikrein transgene expression was detected in the serum and urine of STZ-induced diabetic rats after gene transfer. Kallikrein gene delivery significantly reduced blood glucose levels and cardiac glycogen accumulation in STZ-induced diabetic rats. Kallikrein gene transfer also significantly attenuated elevated plasma triglyceride and cholesterol levels, food and water intake, and loss of body weight gain, epididymal fat pad, and gastrocnemius muscle weight in STZ-induced diabetic rats. However, these effects were blocked by icatibant, a kinin B2 receptor antagonist. Cardiac function was significantly improved after kallikrein gene transfer as evidenced by increased cardiac output and +/-delta P/delta t (maximum speed of contraction/relaxation), along with elevated cardiac sarco(endo)plasmic reticulum (Ca2+ + Mg2+)-ATPase (SERCA)-2a, phosphorylated phospholamban, NOx and cAMP levels, and GLUT4 translocation into plasma membranes of cardiac and skeletal muscle. Kallikrein gene delivery also increased Akt and glycogen synthase kinase (GSK)-3beta phosphorylation, resulting in decreased GSK-3beta activity in the heart. These results indicate that kallikrein through kinin formation protects against diabetic cardiomyopathy by improving cardiac function and promoting glucose utilization and lipid metabolism.     

Electroporation-mediated HGF gene transfer ameliorated cyclosporine nephrotoxicity

BACKGROUND: The clinical utility of cyclosporine A (CsA) has been limited by its nephrotoxicity, which is characterized by tubular atrophy, interstitial fibrosis, and progressive renal impairment. Hepatocyte growth factor (HGF) has been reported to protect and salvage from renal injury as a renotropic and antifibrotic factor. Here, we investigated protective effects of HGF gene therapy on rat CsA-induced nephrotoxicity using electroporation-mediated gene transfer. METHOD: CsA was subcutaneously administered daily under low sodium diet, and HGF gene was transferred into skeletal muscle by electroporation on days 7 and 14. We also examined the antiapoptotic mechanism of HGF using human proximal tubular epithelial cells. RESULTS: HGF gene transfer rescued CsA-induced initial tubular injury and suppressed interstitial infiltration of ED-1-positive macrophages in CsA-induced nephrotoxicity. In addition, HGF significantly inhibited tubular cell apoptosis, and increased the number of proliferating tubular epithelial cells. In vitro studies suggest that HGF executes the antiapoptotic function by enhancing the phosphorylation of Akt and Bcl-2. Northern blot analysis demonstrated that HGF gene transfer suppressed cortical mRNA levels of transforming growth factor-beta (TGF-beta). Consequently, HGF gene transfer significantly reduced a striped interstitial phenotypic alteration and fibrosis. CONCLUSION: We demonstrated that HGF gene transfer reduced CsA-induced tubular cell apoptosis and interstitial fibrosis. HGF gene transfer could be a potential strategy for preventing renal fibrosis.     

Antimicrobial gentamicin activity in the presence of exogenous protease inhibitor (Bowman-Birk inhibitor) in gentamicin-induced nephrotoxicity in rats.

In our previous studies, we found increased levels of urinary trypsin inhibitory activity in gentamicin-induced nephrotoxicity in rats. Following administration of the Bowman-Birk trypsin and chymotrypsin inhibitor (BBI), no proteinuria was detected in gentamicin-treated rats, and a decrease in creatinine clearance was noted in only 50% of the injected rats. In the present study, we examined the antimicrobial activity of gentamicin against Escherichia coli in the presence of BBI in gentamicin-induced nephrotoxicity in rats. We found that 50% of rats with E. coli-positive blood cultures died of septicemia. All the rats injected with E. coli plus gentamicin or E. coli plus gentamicin plus BBI survived, the latter showing no proteinuria or deterioration in creatinine clearance. In conclusion, BBI, which is an effective inhibitor of gentamicin-induced nephrotoxicity, does not affect the antimicrobial activity of gentamicin sulfate.     

Renoprotective effect of Hemidesmus indicus, a herbal drug used in gentamicin-induced renal toxicity

BACKGROUND AND AIMS: Owing to the global trend towards improved 'quality of life', there is considerable evidence of an increase in demand for medicinal plants. The WHO guidelines define basic criteria for the standardization of herbal medicines. The present work is an effort in this direction to prove the safety and efficacy of Hemidesmus indicus Linn. in the management of nephrotoxicity induced by aminoglycosides such as gentamicin. METHODS AND RESULTS: Simple, quality control methods using high performance thin layer chromatographic (HPTLC) phytochemical fingerprint, proximate analysis, and the stability of the H. indicus root powder were developed. From the toxicity study using albino Swiss mice, it was observed that the drug (H. indicus) was relatively safe up to 7 g/kg bodyweight dose. Efficacy was evaluated against gentamicin-induced nephrotoxicity in albino Wister rats. The study examined animals from the following groups: no treatment, gentamicin treated, gentamicin treated recovery, and gentamicin and plant treated. Animals from all groups were killed on day 13 of the study; those from gentamicin treated group were killed on the seventh day. Assessment of the drug efficacy drug was conducted by using haematological and histological examination. CONCLUSION: The treatment with H. indicus helped in the management of renal impairment, which was induced by gentamicin in rats. This is evident from the results obtained for various kidney function tests for gentamicin, along with the results from the plant treated group, and is in comparison with the results found for the gentamicin recovery group. A histological examination of kidneys also supports the findings from haematological evaluations. The plant shows promise as an adjunct therapy along side aminoglycosides as it reduces nephrotoxicity caused by aminoglycosides.     

Amelioration of gentamicin nephrotoxicity by phospholipids.

The effect of phospholipids on gentamicin-induced nephrotoxicity was studied in Sprague-Dawley rats. Group 1a (5 rats) were given daily intraperitoneal injections of 100 mg/kg of gentamicin and sacrificed on day 7. Group 1b (10 rats) were similarly treated but were sacrificed on day 14. Group 2a (5 rats) were given 30 mg/kg of phospholipids for 6 days and sacrificed on day 7, serving as phospholipid controls. Group 2b (5 rats) were similarly treated, and from day 7 onwards daily intraperitoneal injections of 100 mg/kg of gentamicin were given while oral phospholipids were continued until the rats were sacrificed 7 days after gentamicin treatment. Group 2c (10 rats) were treated in the same manner as group 2b but the animals were sacrificed on day 28 after gentamicin treatment. Group 3 (10 rats) were given 30 mg/kg of phospholipids concurrently with intraperitoneal gentamicin injections and were sacrificed on day 28. Protein concentrations, N-acetyl-beta-glucosaminidase (NAG) activities and creatinine were measured in 24-h urine samples. Serum creatinine concentrations were measured in blood samples and 24-h creatinine clearance calculated. Gentamicin concentrations were determined in kidney tissues from which sections were also taken for light- and electron-microscopy. Results showed that gentamicin induced a marked increase in NAG and protein excretion, and a marked decrease in creatinine clearance with six rats succumbing to uraemia. Phospholipid treatment, whether started before or concurrently with gentamicin injections, reduced gentamicin-induced nephrotoxicity. The rats did not lose weight. Urinary excretion of NAG and protein was significantly reduced.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of efficacy of vitamin E and N-acetyl cysteine in gentamicin-induced nephrotoxicity 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. This study was designed to investigate treatment and posttreatment renoprotective potential of vitamin E and N-acetyl cysteine (NAC) against GM-induced oxidative stress and renal dysfunction. Male Sprague-Dawley rats were divided into six groups: first group is the control group that received olive oil (0.1 mL/100 g B.W.), second is the one that was treated with GM (80 mg/kg/i.p./8 days), third is the one that was treated with GM (80 mg/kg/i.p./8 days) and vitamin E (50 mg/kg/i.p./8 days), fourth is the one that was treated with GM (80 mg/kg/i.p./8 days) and NAC (50 mg/kg/i.p./8 days), fifth is the one that was treated with GM (80 mg/kg/i.p./8 days), vitamin E (50 mg/kg/i.p./8 days), and NAC (50 mg/kg/i.p./8 days), and sixth is the one that was treated with GM initially for 8 days (at 80 mg/kg/i.p.) after which vitamin E (at 50 mg/kg/i.p.) and NAC (at 50 mg/kg/i.p.) were administered for 8 days. Serum creatinine, blood urea nitrogen, serum glucose, renal malondialdehyde, renal reduced glutathione, urine sodium, fractional excretion of sodium, and histopathological examination of kidney were performed after treatment. Gentamicin treatment caused nephrotoxicity as evidenced by marked elevation in serum creatinine, blood urea nitrogen, renal malondialdehyde, urine sodium, and fractional excretion of sodium. Study of renal morphology showed marked loss of epithelium in proximal convoluted tubule, inflammatory infiltrate in the form of lymphocytes, mainly in interstitium. Treatment and posttreatment with vitamin E and NAC significantly restored renal functions, reduced lipid peroxidation, enhanced reduced glutathione level, and restored the biochemical parameters. The results of this study demonstrate the therapeutic potential of vitamin E and NAC in gentamicin-induced nephrotoxicity.     

Poly(ADP-ribose) polymerase 1 activation is required for cisplatin nephrotoxicity

Apoptosis, necrosis, and inflammation are hallmarks of cisplatin nephrotoxicity; however, the role and mechanisms of necrosis and inflammation remains undefined. As poly(ADP-ribose) polymerase 1 (PARP1) inhibition or its gene deletion is renoprotective in several renal disease models, we tested whether its activation may be involved in cisplatin nephrotoxicity. Parp1 deficiency was found to reduce cisplatin-induced kidney dysfunction, oxidative stress, and tubular necrosis, but not apoptosis. Moreover, neutrophil infiltration, activation of nuclear factor-κB, c-Jun N-terminal kinases, p38 mitogen-activated protein kinase, and upregulation of proinflammatory genes were all abrogated by Parp1 deficiency. Using proximal tubule epithelial cells isolated from Parp1-deficient and wild-type mice and pharmacological inhibitors, we found evidence for a PARP1/Toll-like receptor 4/p38/tumor necrosis factor-α axis following cisplatin injury. Furthermore, pharmacological inhibition of PARP1 protected against cisplatin-induced kidney structural/functional damage and inflammation. Thus, our findings suggest that PARP1 activation is a primary signal and its inhibition/loss protects against cisplatin-induced nephrotoxicity. Targeting PARP1 may offer a potential therapeutic strategy for cisplatin nephrotoxicity.     

Reduction of the drug-induced nephrotoxicity by ATP-MgCl2. II. Effects on gentamicin-treated isolated perfused kidneys

Drug-induced nephrotoxicity (NT) has become an increasingly significant clinical problem. An in vitro model of drug-induced NT was therefore developed using gentamicin and the effects of ATP-MgCl2 on reduction or prevention of NT were determined. To study this, non-pulsatile perfusion in isolated rat kidneys was maintained at 100 mm Hg during 2 hr of perfusion at 37 degrees C. The oxygenated Krebs-HCO3 perfusate contained 7.5 g/dl albumin as colloid, glucose, creatinine, amino acids, trace amounts of [3H]inulin and 125I-lysozyme, and either 0, 0.4, 0.8, or 1.2 mg/ml of gentamicin. In some studies, 2 mM ATP-MgCl2 was added with 0.8 mg/ml of gentamicin at 0 and 60 min of perfusion. During each 10-min clearance period, glomerular filtration rates, sodium absorption, water absorption, and fractional clearance of TCA-precipitable lysozyme were measured. The results indicate that renal perfusate flow, glomerular filtration rate, urinary flow and tubular absorption of protein (a sensitive indicator of tubular function), sodium, and water were affected by gentamicin in a dose-dependent manner. An isolated kidney preparation can therefore be used to study gentamicin-induced NT. Higher in vitro perfusate concentrations of the drug were needed, however, to acutely mimic the in vivo cumulative effects. Nonetheless, renal perfusate flow, glomerular filtration rate, and the depression in protein reabsorption which occurred with gentamicin treatment were markedly improved by simultaneous treatment with ATP-MgCl2. Thus, ATP-MgCl2 may be useful in reducing drug-induced nephrotoxicity.     

Renoprotective effect of Spirulina fusiformis on cisplatin-induced oxidative stress and renal dysfunction in rats

Cisplatin is an effective chemotherapeutic agent used in the treatment of a wide array of both pediatric and adult malignancies. Dose-dependent and cumulative nephrotoxicity is the major toxicity of this compound, sometimes requiring a reduction in dose or discontinuation of treatment. Recent evidences have implicated oxidative and nitrosative stress in cisplatin-induced nephrotoxicity. Spirulina fusiformis, blue-green algae, is claimed to be a potential antioxidant. The present study was designed to explore the renoprotective potential of Spirulina fusiformis against cisplatin-induced oxidative stress and renal dysfunction. Spirulina fusiformis (500,1000,1500 mg/kg(-1) p.o.) was administered 2 days before and until 3 days after cisplatin challenge (5 mg/kg(-1) i.p.). Renal injury was assessed by measuring serum creatinine, blood urea nitrogen, creatinine and urea clearance, and serum nitrite levels. Renal oxidative stress was determined by renal TBARS levels, reduced glutathione levels, and by enzymatic activity of superoxide dismutase and catalase. A single dose of cisplatin produced marked renal oxidative and nitrosative stress and significantly deranged renal functions. Chronic Spirulina fusiformis treatment significantly and dose-dependently restored renal functions, reduced lipid peroxidation, and enhanced reduced glutathione levels, superoxide dismutase, and catalase activities. The results of the present study clearly demonstrate the pivotal role of reactive oxygen species and their relation to renal dysfunction and point to the therapeutic potential of Spirulina fusiformis in cisplatin-induced nephrotoxicity.     

Parathyroid hormone enhances gentamicin uptake by opossum kidney cells but not by LLC-PK1 cells.

Parathyroidectomy is proposed to be protective against gentamicin nephrotoxicity in rats. In the present study, we evaluated the effects of bovine PTH(1-34) on gentamicin accumulation in cultured kidney epithelial cell lines, opossum kidney (OK) cells which possess PTH receptors and LLC-PK1 cells which are devoid of PTH receptors. Ten days after seeding, the culture medium was exchanged for medium containing 1 mM gentamicin and bovine PTH. The cell gentamicin concentration was measured by a substrate-labeled fluorescence immunoassay (TDA gentamicin kit). Gentamicin uptake was accelerated by bovine PTH in OK cells but not in LLC-PK1 cells. The enhancing effect of bovine PTH seems to be mediated by a cAMP-dependent process. The results suggest that PTH accelerates gentamicin accumulation in renal tissues and potentiates gentamicin nephrotoxicity.     

Protective effect of hydroalcoholic extract of Pistacia vera against gentamicin-induced nephrotoxicity in rats

Purpose: Pistacia vera is a plant of the family Anacardiaceae found in Central and West Asia. P. vera nut (Pistachio) possess multiple pharmacological effects such as antimicrobial, anti-hyperlipidemia, antioxidant and anti-inflammatory. This study is designed to evaluate the protective effect of the hydroalcoholic extract of pistachio on gentamicin-induced nephrotoxicity in rats.

Methods: Nephrotoxicity was induced in rats by intraperitoneal injection of gentamicin (100?mg/kg/day for 7?days). Hydroalcoholic extract of pistachio (10, 50 and 100?mg/kg/p.o) was administered for 7?days. The nephroprotective activity was evaluated by determining creatinine clearance, serum creatinine, urine volume, urine glucose and blood urea nitrogen (BUN) levels. The kidneys were processed for histopathological examinations and all specimens were examined for morphologic parameters involving tubular degeneration, tubular necrosis and tubule interstitial nephritis.

Results: Results showed a significant increase in the levels of serum creatinine, urine volume, urine glucose and BUN and decrease of creatinine clearance by gentamicin (GA) administration. Co-administration with pistachio extract showed reduction in the levels of serum creatinine, urine volume, urine glucose and BUN and increase of creatinine clearance in all doses but the most significant alteration was observed in doses of 100?mg/kg. Also, the nephroprotective effect of the GA was confirmed by the histological examination of the kidneys.

Conclusion: The study revealed the nephroprotective effect of the hydroalcoholic extract of pistachio. These findings suggest that pistachio treatment may attenuate renal dysfunction and structural damage through the reduction of oxidative stress and inflammation in the kidney.