Glycerol-induced Acute Renal Failure In Rats Research Articles

The Structure and Nephroprotective Activity of Oligo-Porphyran on Glycerol-Induced Acute Renal Failure in Rats.

Porphyran is a sulfate galactan in the cell wall of Porphyra. Its acid hydrolysis product, oligo-porphyran (OP), was prepared and the structure studied by electrospray ionization time-of-flight mass spectrometry (ESI-TOF-MS). This oligosaccharide was mainly composed of monosulfate-oligo-galactan, disufate-oligo-galactan, trisulfate-oligo-galactan, trisulfate oligo-methyl-galactan, and 3,6-anhydrogalactose with the degree of polymerization ranging from 1 to 8. The effects of OP were investigated in the glycerol-induced acute renal failure (ARF) model. Compared with the normal group, rats from the glycerol-induced group exhibited collecting duct and medullary ascending limb dilation and casts. The OP-treated group exerted a protective effect against glycerol-induced changes. The results showed that the administration of OP markedly decreased mortality in female ARF rats. For male ARF rats, all of which survived, OP significantly decreased the blood urea nitrogen and serum creatinine levels. Ion levels in plasma and urine were significantly changed in ARF rats, whereas OP treatment almost recovered ion levels back to normal. This study showed a noticeable renal morphologic and functional protection by OP in glycerol-induced ARF rats.

Modulation of multidrug resistance-associated proteins function in erythrocytes in glycerol-induced acute renal failure rats.

Evaluation of the function of multidrug resistance-associated proteins (MRPs) expressed in erythrocytes and screening of endogenous MRPs modulator(s) in glycerol-induced acute renal failure (ARF) rats. Concentrations of 2,4-dinitrophenyl-S-glutathione (DNP-SG), a substrate for MRPs, in erythrocytes after administration of 1-chloro-2,4-dintrobenzene (CDNB), a precursor of DNP-SG, were determined in control and ARF rats. The screening of endogenous MRPs modulator(s) was performed using washed erythrocytes and inside-out erythrocyte membrane vesicles (IOVs) in vitro. Accumulation of DNP-SG in erythrocytes was observed in ARF rats. Uraemic plasma components exhibited a greater inhibitory effect on DNP-SG uptake by IOVs than control plasma components and increased the DNP-SG accumulation significantly in washed erythrocytes. Several protein-bound uraemic toxins at clinically observed concentrations and bilirubin significantly inhibited DNP-SG uptake by IOVs. In washed erythrocytes, bilirubin (10 μm) and l-kynurenine (100 μm), a precursor of kynurenic acid being MRPs inhibitor, increased DNP-SG accumulation significantly. Glycerol-induced ARF rats contain various MRPs inhibitors in plasma, and membrane-permeable MRP substrates/inhibitors including their precursors inhibit the MRPs function in erythrocytes cooperatively.

L-Citrulline Protects Against Glycerol-Induced Acute Renal Failure in Rats

There is an increasing evidence that oxidative stress plays an important role in the pathogenesis of rhabdomyolysis-induced acute renal failure (ARF). In this study, protective effects of L-citrulline on glycerol-induced ARF in rats were investigated. Six groups of rats were employed in this study: group 1 served as a control; group 2 was only given glycerol (50%, 10 mL/kg, i.m.); group 3 was given glycerol plus dexamethasone (0.1 mg/kg, i.g.) as positive reference drug, starting at the same time as the glycerol injections; the last three groups were given glycerol plus L-citrulline (300, 600, and 900 mg/kg, i.g.) respectively, starting at the same time as the glycerol injections. The injections of glycerol were only once, and after glycerol injections the i.g. administrations of dexamethasone and L-citrulline were repeated every 24 h for 7 days. After 7 days of glycerol injections, the blood samples and kidney tissues were harvested for future biochemical and pathology analyses. The levels of creatinine (Cr) and urea nitrogen (BUN) in plasma, the content of malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO), the activity of total nitric oxide synthase (TNOS), inducible nitric oxide synthase (iNOS), endothelial NO synthase (eNOS), and superoxide dismutase (SOD) were evaluated in kidney tissues. Consequently, administrations of L-citrulline improved an impaired intrarenal oxygenation and kidney function compared with the glycerol group, and prevented the renal oxidative stress damage as well as severe functional and morphological renal deterioration. Therefore, L-citrulline might have potential application in the amelioration of glycerol-induced ARF.

Protective Effect of Ginsenoside against Acute Renal Failure and Expression of Tyrosine Hydroxylase in the Locus Coeruleus

Acute renal failure (ARF) is mainly characterized by acute tubular necrosis. No significant change was found for mortality rates over the past few decades despite significant advances in supportive care. In recent years, great effort has been focused on traditional and herbal medicine, which is much less toxic than those agents conventionally used and which is nowadays considered as a novel therapeutic agent for ARF. However, the effect of ginsenosides (GS) administered orally on ARF has not been reported yet and little is known about its cellular and molecular mechanism. The purpose of the study is to investigate the protective effect of ginsenoside in rats with ARF on the changes of tyrosine hydroxylase immunoreactivity (TH-IR) as well as on the involvement of mitogen-activated protein kinases (MAPK) in the locus coeruleus. In our assay, glycerol-induced acute renal failure in rats was employed to study the protective effects of ginsenoside. Our results indicated that the treatment of ARF rats with ginsenosides for 48 h significantly reduced the serum blood urea nitrogen, creatinine level, and lipid peroxidation, restored the GSH level and the normal renal morphology. Immunohistochemistry showed that an obvious increase of TH-IR was further enhanced in ARF+GS group. The same effect was also observed in the changes of p-ERK1/2-IR in the locus coeruleus. Our results suggest that ginsenoside administered orally may have a strong renal protective effect against glycerol-induced ARF, and ginsenoside can also activate the brain catecholaminergic neurons in the locus coeruleus. Our future attention will be focused to the question whether there is a correlation between the renal protective effect of ginsenosides against acute renal failure and the activation of tyrosine hydroxylase in the locus coeruleus.

Comparative Study of Increased Plasma Quinidine Concentration in Rats with Glyceroland Cisplatin-induced Acute Renal Failure

A comparative study of altered plasma concentration of quinidine in rats with glycerol- and cisplatin-induced acute renal failure (ARF) was conducted with quinidine used as a positively charged and liver-metabolized therapeutic compound. Although apparent total body clearance of quinidine decreased to 68 and 48% of the normal value in glycerol- and cisplatin-induced ARF rats, respectively, its distribution decreased only in glycerol-induced ARF rats. The plasma unbound fraction of quinidine decreased in glycerol-induced ARF rats, which was not observed in cisplatin-induced ARF rats. The plasma level of alpha(1)-acid glycoprotein (AGP) increased in glycerol-induced ARF, but not in cisplatin-induced ARF rats. It is therefore conceivable that the plasma concentration of positively charged and liver-metabolized compounds generally increases due to hepatic elimination suppressed as renal function decreases, but the pharmacokinetic impact of suppressed hepatic elimination is occasionally difficult to observe in some ARF model rats since it may be blurred by the influence of increased plasma AGP level.

Protective Effect of Resveratrol, a Polyphenolic Phytoalexin on Glycerol-Induced Acute Renal Failure in Rat Kidney

Rhabdomyolysis-induced myoglobinuric acute renal failure (ARF) accounts for about 10% to 40% of all cases of ARF. Reactive oxygen intermediates have been demonstrated to play an etiologic role in myoglobinuric renal failure. This study was designed to investigate the effect of resveratrol, a polyphenolic phytoalexin in glycerol-induced ARF in rats. Seven groups of rats were employed in this study, group I served as control; group II was given 50% glycerol (8mL/kg, intramuscularly); groups III, IV, and V were given glycerol plus resveratrol (2mg/kg, 5mg/kg, and 10mg/kg p.o. route, respectively) 60 min prior to the glycerol injection; group VI received L-NAME (10mg/kg, i.p.) along with glycerol and resveratrol (5 mg/kg), group VII animals received L-NAME (10 mg/kg) 30 min prior to glycerol administration. Renal injury was assessed by measuring plasma creatinine, blood urea nitrogen, creatinine, and urea clearance. The oxidative stress was measured by renal malondialdehyde levels and reduced glutathione levels, and by enzymatic activity of catalase, glutathione reductase, and superoxide dismutase. Tissue and urine nitrite levels were measured as an index of total nitric oxide levels. Glycerol treatment resulted in a marked decrease in tissue and urine nitric oxide levels, renal oxidative stress, and significantly deranged the renal functions along with deterioration of renal morphology. Pretreatment of animals with resveratrol (5 and 10 mg/kg) 60 min prior to glycerol injection markedly attenuated the fall in nitric oxide levels, renal dysfunction, morphologic alterations, reduced elevated thiobarbituric acid reacting substances, and restored the depleted renal antioxidant enzymes. This protection afforded by resveratrol was significantly reversed by cotreatment of L-NAME along with resveratrol, clearly indicating that resveratrol exerts its protective effect through nitric oxide release along with the antioxidative effect in glycerol-induced ARF.

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.

Ameliorative Effect of Hepatocyte Growth Factor on Glycerol-Induced Acute Renal Failure with Acute Tubular Necrosis

Background/Aims: Hepatocyte growth factor (HGF), a multi-potent growth factor, is known to promote regeneration of damaged renal epithelial cells. Glycerol injection into rats induces severe acute renal failure (ARF) with ischemia and tubular necrosis, a model which shares many features with human ARF or rhabdomyolysis. We investigated the efficacy of HGF in this glycerol-induced ARF rat model. Methods: ARF was induced by intramuscular injection of glycerol into the hind limbs of male Wistar rats. HGF (0.25 mg/kg/shot) or vehicle was administered intravenously 1 h before and 1, 3, 5, 8, 24 and 36 h after glycerol injection. Biochemical parameters for serum and urine were measured and histological analyses of the kidneys were performed. We also analyzed endogenous HGF expression and phosphorylation of c-Met/HGF receptor in the kidneys of glycerol-induced ARF rats. Results: Glycerol treatment caused severe ARF which invariably led to death of the rats. Repeated administration of HGF protected rats from death caused by severe ARF. Histological analyses revealed that HGF treatment reduced necrosis of tubular cells in the renal cortex. Serum/urine biochemical parameters also showed that renal dysfunction was improved by HGF administration. Intravenous administration of HGF enhanced phosphorylation of the c-Met/HGF receptor and mitogen-activated protein kinase in the kidney. In the vehicle-treated group the renal endogenous HGF concentration decreased and there was no change in c-Met/HGF receptor phosphorylation. Conclusion: These results indicate that HGF effectively accelerated the recovery of renal function and improved survival in glycerol-induced ARF rats.

PRODUCTION AND ACTIVATION OF HEPATOCYTE GROWTH FACTOR IN ACUTE RENAL FAILURE

Hepatocyte growth factor (HGF) facilitates the regeneration of injured kidney in acute renal failure (ARF). HGF is produced as a single-chain precursor by cells of mesenchymal origin and is converted to a biologically active, heterodimeric molecule by proteol ytic processing.We studied HGF mRNA and protein levels in systemic organs of glycerol-induced ARF rats, a model of crush syndrome. HGF protein concentration of tissue homogenate was measured by ELISA. Both mRNA and protein levels were increased in liver and spleen at 24 hours after the glycerol injection whereas HGF protein level was decreased in the injured kidney. Expression of HGF receptor/c-met mRNA was elevated only in the kidney. These results suggest that HGF supplied in an endocrine manner may play an important role in the regenerating process following ARF.Next, we measured serum HGF concentration by ELISA in 8 ARF patients caused by crush syndrome and the molecular size of serum HGF was determined byimmun oblotting. Although serum HGF levels elevated in all patients, the HGF levels did not associate with their prognoses. While a single-chain molecule was predominantly observed in sera from chronic renal failure patients and healthy subjects, the majority of serum HGF was a heterodimeric form in 7 ARF patients. In one patient who developed disseminated intravascular coagulation syndrome and had a poor prognosis, a single-chain molecule was predominant although the serum HGF concentration was equivalent. These data suggest that the activity of proteolytic processing may be also an important factor for the expression of the biological function of HGF.

Protective Effect of a Bioflavonoid Proanthocyanidin-BP1 in Glycerol-Induced Acute Renal Failure in the Rat: Renal Stereological Study

Renal ischemia as well as oxygen metaholites ploy an important role in renal Injury during myoglobinuric acute renal failure (ARF). On the other hand, flavonoids. a diverse group of constituents naturally occurring in plants, have a strong antioxidative activity, and have been implicated in vascular relaxation. In this study the protective effect of a new bioflavonoid proanthocvanidin-BP1 (BP1), extracted from seeds of grapes, was evaluated in glycerol-induced ARF in rats. Stereological methods were used to quantify changes in renal morphology associated with ARF. Volume density of tubular lumen and intratubular cast formations, nuclear parameters (area, diameter, volume) of epithelial cells in the cortical proximal tubules, and glomerular parameters (surface area, diameter, volume, perimeter) were estimated on kidney sections of rats treated either with 50% glycerol (8 ml/kg i.m.) alone. BP1 (20 mg/kg i.p.) in addition to glycerol, or BP1 alone. It was noted that the volume density of tubular lumen and cast formations were significantly lower (p < 0.001) in kidneys of the rats treated with BP1 in addition to glycerol, compared with those treated with glycerol alone. There were no significant differences in glomerular and nuclear parameters between glycerol treated, and BP1 in addition to glycerol treated rats. Renal function was significantly improved in rats treated with BP1 in addition to glycerol. The results suggest that BP1 is a protective agent in glycerol model of ARF. This effect is probably due to the antioxidative activity of BP1 and reduced toxicity of myoglobin in renal tissue. Moreover, it is possible that the ability of BP1 to protect the kidney is dependent upon renal vascular relaxation. The potential beneficial effects of bioflavonoid-BP1 demonstrated in experimental ARF could be considered in therapy of myoglobinuric ARF.

Hepatocyte Growth Factor in Glycerol-induced Acute Renal Failure

Hepatocyte growth factor (HGF) facilitates the regeneration of injured kidney in acute renal failure (ARF). Here we investigated the HGF production in glycerol-induced ARF rats. HGF mRNA expression levels were elevated in liver, spleen, and lung 6-24 h after glycerol injection. Tissue HGF protein levels determined by an enzyme-linked immunosorbent assay also increased in liver and spleen, whereas they decreased in the injured kidney 24 h after injection. Immunohistochemical studies showed that the number of HGF-producing cells did not increase in the liver. HGF receptor/c-Met mRNA levels were elevated only in the kidney. These results indicate that HGF supplied in an endocrine manner may play an important role in the regenerating process following ARF.

Regional haemodynamic effects of dopamine and its prodrugs l‐dopa and gludopa in the rat and in the glycerol‐treated rat as a model for acute renal failure

1. In this study the renal selectivity of dopamine and its prodrugs L-dopa and gludopa, with respect to their effects on regional blood flow, vascular resistance and central haemodynamics was investigated in normal rats and in rats with glycerol-induced acute renal failure (ARF). 2. In normal, anaesthetized rats, dopamine as well as its prodrugs caused a dose-dependent reduction of vascular resistance in the kidney (RR), mesentery (MR) and hindquarters (HQR) (dose range: dopamine: 0.1-5 mumol kg-1 h-1; L-dopa and gludopa: 1-200 mumol kg-1 h-1). Blood pressure and heart rate were affected at the highest dose only. 3. Administration of glycerol induced a preferential renal vasoconstriction; renal blood flow (-60%) and vascular resistance (+190%) were significantly more affected than MR (+40%) and HQR (+60%). This was only ameliorated by a low rate (10 mumol kg-1 h-1) infusion of gludopa: the glycerol-induced reduction of renal flow and increase in RR were significantly attenuated. A high dose of gludopa (100 mumol kg-1 h-1) or any dose of L-dopa or dopamine did not induce this beneficial effect. The glycerol-induced increase in MR and HQR was not attenuated by any of the treatments used. 4. The results indicate that gludopa is not renally selective at a pharmacodynamic level in normal, anaesthetized rats. Contrary to this, a low dose of gludopa does cause a renal selective vasodilatation and reduction of RR in rats with glycerol-induced ARF. This difference could be explained by a difference in renal vascular tone between normal rats and glycerol-induced ARF rats. A high dose ofgludopa does not cause these renal-selective effects: renal resistance and renal flow are at the same level as following glycerol and saline. This is probably due to the systemic effects of the released dopamine.