Protective effect of naringin, a bioflavonoid on glycerol-induced acute renal failure in rat kidney

Rhabdomyolysis-induced myoglobinuric acute renal failure accounts for about 10-40% of all cases of acute renal failure (ARF). Reactive oxygen intermediates have been demonstrated to play an etiological role in myoglobinuric renal failure. This study was designed to investigate the effect of naringin, a bioflavonoid with antioxidant potential, in glycerol-induced ARF in rats. Five groups of rats were employed in this study, group I served as control, group II was given 50% glycerol (8 ml/kg, intramuscularly), group III, IV, and V were given glycerol plus naringin 100, 200, and 400mg/kg p.o. route, respectively) 60 min prior to the glycerol injection. Renal injury was assessed by measuring plasma creatinine, blood urea nitrogen, creatinine, and urea clearance. The oxidative stress was measured by renal malondialdehyde levels, reduced glutathione levels, and by enzymatic activity of catalase, glutathione reductase, and superoxide dismutase. Glycerol treatment resulted in a marked renal oxidative stress and significantly deranged the renal functions. Pretreatment of animals with naringin 60 min prior to glycerol injection markedly attenuated renal dysfunction, morphological alterations, reduced elevated thiobarbituric acid reacting substances (TBARS), and restored the depleted renal antioxidant enzymes. These results clearly demonstrate the role of oxidative stress and its relation to renal dysfunction, and suggest a protective effect of naringin in glycerol-induced renal failure in rats.     

Reversal of experimental myoglobinuric acute renal failure in rats by quercetin, a bioflavonoid

The occurrence of acute renal failure (ARF) following rhabdomyolysis has been put at between 10 and 40% of cases, and accounts for between 3 and 15% of all cases of ARF. Reactive oxygen intermediates have been demonstrated to play an etiological role in myoglobinuric renal failure. This study was performed to explore the protective effect of quercetin, a bioflavonoid, in an experimental model of myoglobinuric ARF in rats. Four groups of rats were employed in this study: group 1 served as control, group 2 was given 50% glycerol (8 ml/kg, i.m.), group 3 was given glycerol + quercetin (2 mg/kg, i.p.), and group 4 was given glycerol + DMSO (the solvent for quercetin, 5 ml/kg, i.p.). Renal injury was assessed by measuring serum creatinine, blood urea nitrogen, creatinine and urea clearance. The oxidative stress was measured by renal malondialdehyde levels, reduced glutathione levels and by enzymatic activity of catalase, glutathione reductase, and superoxide dismutase. Glycerol administration resulted in a marked renal oxidative stress, significantly deranged the renal functions as well as renal cytoarchitecture. All these factors were significantly improved by quercetin treatment. Because of its radical-scavenging and iron-chelating properties, quercetin protected the kidney against the glycerol-induced oxidative stress and resultant renal dysfunction. Based on these results, this study confirms the role of oxidative stress and demonstrates the renoprotective potential of quercetin in this rhabdomyolysis-mimicking model.     

Protective effects of L-carnitine on myoglobinuric acute renal failure in rats

1. Muscle injury (rhabdomyolysis) is one of the causes of acute renal failure (ARF). Iron, free radicals and nitric oxide (NO) play a critical role in the pathogenesis of glycerol-induced myoglobinuric ARF. L-Carnitine is an anti-oxidant and prevents the accumulation of end-products of lipid peroxidation. Therefore, the aim of the present study was to investigate the effects of L-carnitine on myoglobinuric ARF induced by intramuscular (i.m.) hypertonic glycerol injection. 2. Sprague-Dawley rats were divided into three groups. Rats in group 1 (n = 8) were given saline, whereas those in groups 2 (n = 10) and 3 (n = 10) were injected with glycerol (10 mL/kg, i.m.). Concomitant with and 24 h after glycerol injection, L-carnitine (200 mg/kg, i.p.) was administered to group 3 rats. Forty-eight hours after glycerol injection, blood samples and kidney tissues were taken from anaesthetised rats. 3. Plasma creatine kinase (CK) activity, urea, creatinine and NO levels, as well as kidney tissue superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) enzyme activity and malondialdehyde (MDA) and glutathione (GSH) levels, were determined. In the kidney tissue, histopathological changes and iron accumulation in the tubular epithelium were also investigated. 4. Glycerol treatment caused severe ARF: a marked renal oxidative stress, significantly increased CK activity, urea and creatinine levels and decreased plasma NO levels. Histopathological findings in group 2 rats confirmed that there was renal impairment by cast formation and tubular necrosis and a marked increase in iron accumulation in the tubular epithelium. All these factors were significantly improved by L-carnitine supplementation. 5. These results may indicate that L-carnitine treatment protects against functional, biochemical and morphological damage and iron accumulation in glycerol-induced myoglobinuric ARF in rats. In this model, the protective effect of L-carnitine treatment may provide a new insight into the treatment of rhabdomyolysis-related ARF.     

Catechin, a natural antioxidant protects against rhabdomyolysis-induced myoglobinuric acute renal failure.

Rhabdomyolysis-induced myoglobinuric acute renal failure accounts for about 10-40% of all cases of acute renal failure (ARF). Reactive oxygen intermediates have been demonstrated to play an etiological role in myoglobinuric renal failure. This study was performed to explore the protective effect of catechin-a natural antioxidant in an experimental model of myoglobinuric ARF in rats. Four groups of rats were employed in this study, group 1 served as control, group 2 was given 50% glycerol (8 ml kg(-1), i.m.), group 3, glycerol plus catechin (40 mg kg(-1), p.o. for 4 days, twice a day) and group 4 was given only catechin (40 mg kg(-1), p.o.), respectively. Renal injury was assessed by measuring serum creatinine, blood urea nitrogen (BUN), creatinine, and urea clearance. The oxidative stress was measured by renal malondialdehyde (MDA) levels, reduced glutathione levels and by enzymatic activity of catalase, glutathione reductase (GR) and superoxide dismutase (SOD). Glycerol administration resulted in a marked renal oxidative stress, significantly deranged the renal functions as well as renal morphology. All these factors were significantly improved by catechin treatment. Catechin, due to its antioxidative activity, reduced the toxicity of myoglobin in the renal tissues, and thus exerted a renoprotective effect in this rhabdomyolysis mimicking model.     

Carvedilol and trimetazidine attenuates ferric nitrilotriacetate-induced oxidative renal injury in rats

Intraperitoneal (i.p.) injection of ferric nitrilotriacetate (Fe-NTA) induces acute proximal tubular necrosis as a consequence of lipid peroxidation and oxidative tissue damage, which eventually leads to high incidence of renal adenocarcinoma in rodents. This study was designed to investigate the effect of carvedilol, an antihypertensive and trimetazidine, an antiischemic, both the drugs with additional antioxidative potentials, on Fe-NTA induced nephrotoxicity in rats. One hour after a single i.p. injection of Fe-NTA (8 mg iron per kg), a marked deterioration of renal architecture and renal function as evidenced by a sharp increase in blood urea nitrogen (BUN) and serum creatinine was observed. Fe-NTA induced a significant renal oxidative stress demonstrated by elevated thiobarbituric acid reacting substances (TBARS) and reduction in activities of renal catalase, superoxide dismutase (SOD) and glutathione reductase (GR). Pretreatment of animals with carvedilol (2 mg/kg, i.p.) as well as with trimetazidine (3 mg/kg, i.p.), 30 min before Fe-NTA administration markedly attenuated renal dysfunction, reduced elevated TBARS, restored the depleted renal antioxidant enzymes and normalised the renal morphological alterations. These results clearly demonstrate the role of oxidative stress and its relation to renal dysfunction, and suggest a protective effect of carvedilol and trimetazidine on Fe-NTA-induced nephrotoxicity in rats.     

Dietary curcumin does not protect kidney in glycerol-induced acute renal failure.

Generation of reactive oxygen species significantly contribute to the pathogenesis of renal injury induced by myoglobin release. The present study was performed to investigate the effects of dietary curcumin, a natural antioxidant isolated from plant Curcuma longa, in an experimental model of myoglobinuric acute renal failure. Rats received curcumin at an oral dose of 100mg/kg/day for 30 days. Renal injury was induced with injection of hypertonic glycerol (10 ml/kg 50% solution) in hind limb muscle with blood urea of 57.8+/-7.2 vs. 7.72+/-1.03 mmol/l and serum creatinine of 444.4+/-61.3 vs. 51.8+/-10.6 micromol/l, in glycerol-induced acute renal failure (ARF) vs. control rats, respectively. After 48 h rats were sacrificed and thiobarbituric acid reactive substance (TBARS), glutathione, carbonyl content and kidney cortex brush border peptidase activities were determined in serum, kidney and liver. Rats that received curcumin in addition to glycerol had significantly lower TBARS in serum but not in kidney and liver. Carbonyl content in kidney and liver was significantly elevated in curcumin and glycerol treated rats and improved in animals treated with curcumin and glycerol together. The activities of kidney cortex enzymes, aminopeptidase N, angiotensinase A and dipeptidyl peptidase IV, were reduced in glycerol as well as in curcumin treated rats. The results obtained in this study provided additional evidence that despite its limited antioxidant activity curcumin did not protect kidney in myoglobinuric model of ARF.     

Nephrotoxicity and its prevention by catechin in ferric nitrilotriacetate promoted oxidative stress in rats

Intraperitoneal injection of ferric nitrilotriacetate (Fe-NTA) to rats and mice results in iron-induced free radical injury and cancer in kidneys. This study was designed to investigate the effect of catechin, a bioflavonoid with antioxidant potential, on Fe-NTA-induced nephrotoxicity in rats. Four groups were employed in the present study. Group I served as control group, Group II animals received Fe-NTA (8 mg iron/kg body weight i.p.), Group III animals were given 40 mg/kg catechin p.o. twice a day for 4 days and on the 5th day Fe-NTA was challenged, and Group IV animals received catechin alone for 4 days. Renal function was assessed by measuring plasma creatinine and blood urea nitrogen. The oxidative stress was measured by renal malondialdehyde levels, reduced glutathione levels and by enzymatic activity of catalase, glutathione reductase and superoxide dismutase. One hour after a single intraperitoneal (i.p.) injection of Fe-NTA (8 mg iron/kg), a marked deterioration of renal architecture, renal function and severe oxidative stress was observed. Pretreatment of animals with catechin markedly attenuated renal dysfunction, reduced elevated thiobarbituric acid reacting substances (TBARS), restored the depleted renal antioxidant enzymes and normalized the renal morphological alterations. These results clearly demonstrate the role of oxidative stress and its relation to renal dysfunction, and suggest a protective effect of catechin on Fe-NTA-induced nephrotoxicity in rats.     

Effects of caffeic acid phenethyl ester on glycerol-induced acute renal failure in rats

1. Free radicals and nitric oxide (NO) play a crucial role in the pathogenesis of myoglobinuric acute renal failure (ARF). The aim of the present study was to investigate the effects of caffeic acid phenethyl ester (CAPE), an anti-oxidant, on the myoglobinuric ARF induced by intramuscular hypertonic glycerol injection. 2. Thirty rats were divided equally into three groups. Rats in group 1 were given saline and those in groups 2 and 3 were injected with glycerol (10 mL/kg, i.m.). Concomitant and 24 h after glycerol injection, CAPE (10 micromol/kg, i.p.) was administered to group 3 rats. Forty-eight hours after glycerol injection, blood samples and kidney tissues of rats were taken under anaesthesia. 3. Plasma concentrations of urea, creatinine, malondialdehyde (MDA) and NO were determined, as were superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities and MDA levels in kidney tissues. Kidney morphology was also investigated. 4. In the group receiving CAPE, although SOD enzyme activity was found to be increased, we failed to find any protective effect of CAPE on other parameters investigated. Moreover, although CAPE significantly decreased NO levels, it increased plasma concentrations of urea and MDA. 5. We suggest that the effect of CAPE in decreasing NO concentrations may further increase the renal ischaemia in this model. Thus, CAPE may have a worsening rather than beneficial effect under these conditions in this model of ARF.     

RETRACTED: Effect of trimetazidine on renal ischemia/reperfusion injury in rats

There is increasing evidence to suggest that toxic oxygen radicals play a role in the pathogenesis of ischemia/reperfusion (I/R) injury in the kidney. This study was designed to investigate the effects of trimetazidine, in I/R induced renal failure in rats. The protective effect of trimetazidine (Tmz) against the damage inflicted by reactive oxygen species (ROS) during renal I/R was investigated in Sprague-Dawley rats using histopathological and biochemical parameters. In one set of experiments animals were unilaterally nephrectomized, and subjected to 45 min of left renal pedicle occlusion and in another set both the renal pedicles were occluded for 45 min followed by 24 h of reperfusion. Trimetazidine (3 mg kg(-1), i.p.) was administered 30 min prior to ischemia and repeated 12 h after the first dose. At the end of the reperfusion period, rats were sacrificed. Thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) levels, glutathione reductase (GR) catalase (CAT), and superoxide dismutase (SOD) activities were determined in renal tissue. Serum creatinine and blood urea nitrogen (BUN) concentrations were measured for the evaluation of renal function. Ischemic control animals demonstrated severe deterioration of renal function, renal morphology and a significant renal oxidative stress. Pretreatment of animals with trimetazidine markedly attenuated renal dysfunction, morphological alterations, reduced elevated TBARS levels and restored the depleted renal antioxidant enzymes. The findings imply that ROS play a causal role in I/R induced renal injury and trimetazidine exert renoprotective effects probably by the radical scavenging and antioxidant activities.     

Amelioration of glycerol-induced acute renal failure in the rat with 8-phenyltheophylline: timing of intervention

The importance of timing and duration of 8-phenyltheophylline (8-PT) administration in determining its beneficial action in glycerol-induced acute renal failure (ARF) was investigated by examining the effects of a single dose of 8-PT given immediately following (0 h) glycerol injection and at 1 and 3 h after glycerol injection. 8-PT when given at 0 h significantly lowered plasma urea and creatinine concentrations and significantly increased inulin clearance when compared both to untreated animals and those that received the vehicle for the drug. By contrast, 8-PT when administered at 1 h afforded no protective effect on renal function and, when injected at 3 h, the only significant effect was lowered plasma creatinine levels when compared to untreated rats; at this latter time it did not lower plasma urea levels or improve inulin clearance. None of the 8-PT injections attenuated the increase in kidney weight associated with ARF or reduced the kidney damage as assessed by histological examination. The results show that a single administration of 8-PT made immediately following glycerol injection can ameliorate the biochemical and functional indices of impaired renal function, but does not produce an improvement in kidney morphology.     

阿魏酸钠对甘油致小鼠肾脏氧化性损伤的拮抗效应阿魏酸钠对甘油致小鼠肾脏氧化性损伤的拮抗效应

目的从氧化应激角度,探讨阿魏酸钠对实验动物中毒性肾损害的防治作用。方法建立甘油所致小鼠急性肾小管损伤模型,观察不同剂量的阿魏酸钠对肾损伤小鼠肾功能指标、抗氧化指标和组织学的影响。结果在甘油注射后6和72 h,阿魏酸钠100～200 mg·kg^-1 ip能剂量依赖性的降低甘油所致血清尿素氮、肌酐和N-乙酰-β-葡糖苷酶的升高。阿魏酸钠200 mg·kg^-1减少肾组织丙二醛生成,提高肾脏谷胱甘肽含量及谷胱甘肽过氧化物酶、谷胱甘肽S-转移酶、过氧化氢酶和超氧化物歧化酶活性,且可明显减轻肾组织病理改变。结论阿魏酸钠对甘油致肾损伤有防治作用,其机制与增强肾脏抗氧化功能有关。     

Attenuation of renal ischemia-reperfusion injury by trimetazidine: evidence of an in vivo antioxidant effect

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 antiischemic agent trimetazidine in a rat model of renal ischemia-reperfusion injury. Renal ischemia-reperfusion was induced by clamping the unilateral renal artery for 45 min followed by 24 h of reperfusion. Trimetazidine (2.5 mg/kg i.p.) was administered 24 and 12 h prior to renal artery occlusion and the same dose was given intravenously 1 h before inducing ischemia. 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 compared with sham operated rats. The ischemic kidneys of rats showed severe hyaline casts, epithelial swelling, proteinaceous debris, tubular necrosis, medullary congestion and hemorrhage. Trimetazidine markedly reduced elevated levels of TBARS and significantly attenuated renal dysfunction and morphological changes in rats subjected to renal ischemia-reperfusion. These results clearly demonstrate the in vivo antioxidant effect and the therapeutic potential of trimetazidine, an anti-ischemic agent, in attenuating renal ischemia-reperfusion injury.     

Quercetin, an anti-oxidant bioflavonoid, attenuates diabetic nephropathy in rats

1. Diabetic nephropathy is an important microvascular complication and one of the main causes of end-stage renal disease. Many in vivo and in vitro studies have indicated that oxidative stress is one of the major pathophysiological mechanisms involved in the development of diabetic nephropathy. In the present study, we examined the effect of an anti-oxidant bioflavonoid quercetin on renal function and oxidative stress in streptozotocin (STZ)-induced diabetic rats. 2. Diabetes was induced in Sprague-Dawley rats with a single intravenous injection of STZ (45 mg/kg). Four weeks after STZ injection, quercetin (10 mg/kg per day) was given orally for 4 weeks in both control and diabetic rats. Plasma glucose levels and bodyweights were measured at 4 and 8 weeks after the STZ injection. At the termination of the experiments, urine albumin excretion, urine output, serum creatinine, blood urea nitrogen, creatinine and urea clearance were measured. The renal oxidative stress marker malonaldehyde, glutathione levels and the anti-oxidant enzymes superoxide dismutase and catalase were measured in kidney homogenate. 3. Streptozotocin-injected rats showed significant increases in blood glucose, polyuria, proteinuria and a decrease in bodyweight compared with age-matched control rats. After 8 weeks, diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine and urea clearance, and proteinuria along with a marked increase in oxidative stress, as determined by lipid peroxidation and activities of key anti-oxidant enzymes. Treatment with quercetin significantly attenuated renal dysfunction and oxidative stress in diabetic rats. 4. These results confirm the role of oxidative stress in the development of diabetic nephropathy and point to the possible anti-oxidative mechanism being responsible for the nephroprotective action of quercetin.     

Lycopene, a carotenoid, attenuates cyclosporine-induced renal dysfunction and oxidative stress in rats

The aim of this study was to investigate the possible protective role of antioxidant treatment with lycopene on cyclosporine A-induced nephrotoxicity using biochemical and histopatological approaches. Adult male Sprague-Dawley rats were randomly divided into four groups. The control group received physiological saline; animals in the lycopene group received only lycopene (10 mg/kg); animals in the cyclosporine A group received only cyclosporine A (15 mg/kg) and animals in cyclosporine plus lycopene group received cyclosporine and lycopene for 21 days. The effects of lycopene on cyclosporine A-induced nephrotoxicity were evaluated by plasma creatinine, urea, sodium and calcium concentrations; kidney tissue thiobarbituric acid reactive species, reduced glutathione (GSH), glutathione peroxidase (GSH-Px) and catalase activities and histopatological examinations. Administration of cyclosporine A to rats induced a marked renal failure, characterized with a significant increase in plasma creatinine and urea concentrations. Cyclosporine A also induced oxidative stress as indicated by increased kidney tissue concentrations of thiobarbituric acid reactive species and GSH, and reduced activities of GSH-Px and catalase. Moreover, the kidneys of cyclosporine A-treated rats showed tubular necrosis, degeneration, dilatation, thickened basement membranes, luminal cast formation and inter-tubular fibrosis. Lycopene markedly reduced elevated plasma creatinine, urea levels and counteracted the deleterious effects of cyclosporine A on oxidative stress markers. In addition, lycopene ameliorated cyclosporine A-induced pathological changes including tubular necrosis, degeneration, thickened basement membranes and inter-tubular fibrosis when compared to the alone cyclosporine A group. These data indicate that the natural antioxidant lycopene might have protective effect against cyclosporine-induced nephrotoxicity and oxidative stress in rat.     

Tephrosia purpurea ameliorates N-diethylnitrosamine and potassium bromate-mediated renal oxidative stress and toxicity in Wistar rats.

In an earlier communication, we have shown that Tephrosia purpurea ameliorates benzoyl peroxide-induced oxidative stress in murine skin (Saleem et al. 1999). The present study was designed to investigate a chemopreventive efficacy of T purpurea against N-diethylnitrosamine-initiated and potassium bromate-mediated oxidative stress and toxicity in rat kidney. A single intraperitoneal dose of N-diethylnitrosamine (200 mg/kg body weight) one hr prior to the dose of KBrO3 (125 mg/kg body weight) increases microsomal lipid peroxidation and the activity of xanthine oxidase and decreases the activities of renal antioxidant enzymes viz., catalase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase, phase II metabolizing enzymes such as glutathione-S-transferase and quinone reductase and causes depletion in the level of renal glutathione content. A sharp increase in blood urea nitrogen and serum creatinine has also been observed. Prophylactic treatment of rats with T. purpurea at doses of 5 mg/kg body weight and 10 mg/kg body weight prevented N-diethylnitrosamine-initiated and KBrO3 promoted renal oxidative stress and toxicity. The susceptibility of renal microsomal membrane for iron ascorbate-induced lipid peroxidation and xanthine oxidase activities were significantly reduced (P<0.01). The depleted levels of glutathione, the inhibited activities of antioxidant enzymes, phase II metabolizing enzymes and the enhanced levels of serum creatinine and blood urea nitrogen were recovered to a significant level (P<0.01). All the antioxidant enzymes were recovered dose-dependently. Our data indicate that T purpurea besides a skin antioxidant can be a potent chemopreventive agent against renal oxidative stress and carcinogenesis induced by N-diethylnitrosamine and KBrO3.     

Protective effect of γ-aminobutyric acid against glycerol-induced acute renal failure in rats

To investigate the effect of γ-aminobutyric acid (GABA) on acute renal failure, we used a rat model of acute tubular necrosis induced by glycerol. After deprivation of water for 6 h, the rats received an injection of 50% glycerol into the muscle of the rear limb at 10 ml/kg body weight. GABA was then administered orally to the rats (100 or 500 mg/kg body weight/day) once every 12 h for 3 days. The rats with acute renal failure showed arrested body weight gain and an increase of kidney weight, whereas oral administration of GABA attenuated the physiological changes induced by acute renal failure. However, GABA administration had no significant effect on increased urine volume. Oral administration of GABA at a dose of 100 or 500 mg/kg body weight/day for 3 days significantly improved the markedly elevated levels of blood urea nitrogen and creatinine and the reduced creatinine clearance related to progression of renal failure. Moreover, the rats with acute renal failure exhibited high levels of fractional excretion of sodium (FE_Na) due to alteration of tubule function following injection of glycerol. However, administration of GABA lowered the FE_Na levels dose-dependently. Furthermore, urine osmolarity was markedly reduced in control rats with acute renal failure as compared with normal rats, whereas it was significantly increased by administration of GABA at a dose of 500 mg/kg body weight/day. These results indicate that GABA has potential as a therapeutic agent against the renal damage involved in acute renal failure.     

Pharmacological investigations of Punica granatum in glycerol-induced acute renal failure in rats

Objective:

The present study was designed to investigate the ameliorative potential and possible mechanism of hydroalcoholic extract of flowers of P. granatum in glycerol-induced acute renal failure (ARF) in rats.

Materials and Methods:

The rats were subjected to rhabdomyolytic ARF by single intramuscular injection of hypertonic glycerol (50% v/v; 8 ml/kg) and the animals were sacrificed after 24 hours of glycerol injection. The plasma creatinine, blood urea nitrogen, creatinine clearance, and histopathological studies were performed to assess the degree of renal injury.

Results:

Pretreatment with hydroalcoholic extract of flowers of P. granatum (125 and 250 mg/kg p.o. twice daily for 3 days) significantly attenuated hypertonic glycerol-induced renal dysfunction in a dose-dependent manner. BADGE (Bisphenol-A-diglycidyl ether) (30 mg/kg), a peroxisome proliferator-activated receptor (PPAR)-γ antagonist, and N(omega)-nitro-l-arginine-methyl ester (L-NAME) (10, 20, and 40 mg/kg), nitric oxide synthase inhibitor, were employed to explore the mechanism of renoprotective effects of Punica granatum. Administration of BADGE (30 mg/kg) and L-NAME (40 mg/kg) abolished the beneficial effects of P. granatum in glycerol-induced renal dysfunction.

Conclusion:

Hydroalcoholic extract of flowers of P. granatum has ameliorative potential in attenuating myoglobinuric renal failure and its renoprotective effects involve activation of PPAR-γ and nitric oxide-dependent signaling pathway.     

Montelukast abrogates rhabdomyolysis-induced acute renal failure via rectifying detrimental changes in antioxidant profile and systemic cytokines and apoptotic factors production

In addition to antiasthmatic effect, the cysteinyl leukotriene receptor 1 (CysLT?) antagonist montelukast shows renoprotective effect during ischemia/reperfusion and cyclosporine-induced renal damage. Here, we proposed that montelukast protects against rhabdomyolysis-induced acute renal failure. Compared with saline-treated rats, at 48 h following the induction of rhabdomyolysis using intramuscular glycerol (10 ml 50% glycerol/kg), significant elevations in serum levels of urea, creatinine, phosphate and acute renal tubular necrosis were observed. This was associated with elevations in serum Fas, interleukin-10, tumor necrotic factor-alpha, and transforming growth factor-beta1 and renal malondialdehyde and nitrite and detrimental reductions in renal catalase and superoxide dismutase activities. The effects of rhabdomyolysis on renal functional, biochemical and structural integrity and the associated changes in cytokines and Fas levels were abolished upon concurrent administration of montelukast (10 mg/kg i.p.) for 3 days (1 day before and 2 days after induction of rhabdomyolysis). Alternatively, administration of the anti-oxidant, α-tocopherol (400 mg/kg i.m.) for 3 days, succeeded in alleviating renal oxidative stress, but had no significant effect on the circulating levels of most cytokines and partially restored kidney functional and structural damage. Serum level of interleukin-6 was not altered by rhabdomyolysis but showed significant elevations in rats treated with montelukast or α-tocopherol. Collectively, motelukast abrogated functional and structural renal damage induced by rhabdomyolysis via ameliorating renal oxidative stress and modulation of systemic cytokines and apoptotic factors production. The results of this work are expected to open new avenues for early prevention of rhabdomyolysis-induced acute renal failure using selective CysLT? antagonists such as montelukast.     

Protective effects of FK453, a potent nonxanthine adenosine A1 receptor antagonist,on glycerol-induced acute renal failure in rats

The purpose of the present study was to examine the protective effect of FK453, (+)-(R)-1-[(E)-3-(2-phenylpyrazolo [1,5-a] pyridin-3-yl) acryloyl]-2-piperidine ethanol, a potent non-xanthine (adenosine A₁ receptor antagonist, on glycerol-induced acute renal failure (ARF) in rat in comparison with the effects of FR113452 (S-(-) enantiomer of FK453), 1,3-dipropyl-8-cyclopentyl-xanthine (adenosine A₁ receptor antagonist), theophylline (nonselective adenosine receptor antagonist), CGS15943 [1,2,4] triazolo [1,5-C] quinazolone, adenosine A_2A receptor antagonist), and typical diuretics (hydrochlorothiazide and furosemide). FK453 (1 and 10 mg/kg orally) significantly reduced serum creatinine and urea concentrations in 25% glycerol (10 ml/kg intramuscularly)-induced ARF by protective treatment. The effect was similar to that of 1,3-dipropyl-8-cyclopentyl-xanthine and theophylline. FR113452 and CGS15943 had little effect on serum creatinine and urea concentrations. In contrast, hydrochlorothiazide and furosemide increased serum creatinine and urea concentrations. FK453, hydrochlorothiazide, and furosemide did not have any effect on either serum creatinine or urea concentration in 25% glycerol-induced ARF by therapeutic treatment. In 50% glycerol (10 ml/kg im)-induced ARF, FK453 reduced serum creatinine and urea concentrations, and increased urine volume and creatinine clearance. The results of the present study showed that FK453, a potent nonxanthine adenosine A₁ receptor antagonist, ameliorated glycerol-induced ARF in the rat. The findings support the idea that adenosine is an important factor in the development of glycerol-induced ARF in the rat and that the protective effect of adenosine receptor antagonist is mediated via the adenosine A₁ receptor. Drug Dev. Res. 39:47–53 © 1997 Wiley-Liss, Inc.     

Ameliorative effect of flunarizine in cisplatin-induced acute renal failure via mitochondrial permeability transition pore inactivation in rats

This study was aimed to evaluate the protective effect of flunarizine on cisplatin-induced acute renal failure. Administration of cisplatin (6 mg/kg, i.p. on day 6) significantly increased serum blood urea nitrogen and creatinine, urinary N-acetyl β-D-glucosaminidase, tissue thiobarbituric acid reactive substances and total calcium whereas, decreased body weight, fractional excretion of sodium, creatinine clearance tissue-reduced glutathione, mitochondrial cytochrome c oxidase, and ATP levels were observed in acute renal failure rats. Moreover, cisplatin produced histopathological changes in the renal tissue. Furthermore, flunarizine (100, 200, and 300 μM/kg, p.o., for six consecutive days) was administered to evaluate its therapeutic potential in acute renal failure, and the results were compared with cyclosporin A (50 μM/kg, p.o., for six consecutive days) as a reference drug. Flunarizine resulted in the attenuation of cisplatin-induced renal dysfunction, oxidative stress marker, mitochondrial damage, and histopathological changes in rats. Medium and higher doses of flunarizine produced significant renal protective effect which was comparable to cyclosporin A. The results of this study clearly revealed that flunarizine protected the kidney against the nephrotoxic effect of cisplatin via mitochondrial permeability transition pore inactivation potential.