Renal Dysfunction In Rats Research Articles

Pharmacological assessment of delphinidin in counteracting polystyrene microplastic induced renal dysfunction in rats

Polystyrene microplastics (PSMP) are toxic environmental contaminants which can damage various body organs including kidneys. Delphinidin (DEL) is a potential anthocyanidin flavonoid with significant pharmacological benefits. This research was conducted to analyze the protective effect of DEL to avert PSMP prompted renal dysfunction. Rats (n = 24) were divided into 4 separate groups: Control, PSMP (0.01 mgkg−1), PSMP (0.01 mgkg−1) + DEL (25 mgkg−1) and only DEL (25 mgkg−1). Our results showed that PSMP exposure reduced the expressions of Nrf-2 and antioxidant genes while increasing the expression of Keap1. Besides, PSMP intoxication escalated the level of kidney injury markers (urea, KIM-1, creatinine and NGAL) while inducing substantial reduction in the levels of creatinine clearance. Moreover, PSMP significantly reduced the levels of GSH, GST, SOD, HO-1, CAT, GSR, GPx while escalating MDA and ROS. Conversely, inflammatory biomarkers including IL-1β, TNF-α, NF-kB, IL-6 and COX-2 activity were increased due to PSMP intoxication. Our results showed that PSMP administration increased the expressions of Bax and caspase-3 while decreasing the expression of Bcl-2. However, DEL treatment significantly restored the PSMP-induced renal impairments. Therefore, it is suggested that DEL could be used as a therapeutic compound to alleviate PSMP-induced kidney damage in rats, possibly due to its strong pharmacological properties.

Features of Klotho Protein Expression in Rat Kidneys in Experimental Hyperglycemia Against the Background of Pharmacological Correction with GABA Derivatives

The aim is to identify the features of Klotho protein expression in the epithelium of the convoluted tubules of the kidney during prolonged experimental hyperglycemia and pharmacological correction with GABA derivatives. Material and methods. The study used 50 mongrel male rats (initial weight: 330,0–360,0 g) with streptozotocin diabetes lasting 6 months. 6 months after the injection of streptozotocin (60 mg/kg), animals with a glycemic level of ≥ 15 mmol/l were included in the study (after 4 hours of food deprivation), then GABA derivatives (aminalon, mefargine, succicard) were administered orally for 30 days. Proteinuria and serum creatinine concentrations were evaluated. After euthanasia, kidney tissue was fixed in buffered neutral formalin and examined using immunofluorescence microscopy. The intensity of the glow was evaluated based on a visual-analog scale. Results. In the group with chronic hyperglycemia without treatment, there was a significant increase in the protein content in daily urine and serum creatinine levels (p<0,05). In the group of animals with chronic hyperglycemia without treatment, there was a significant decrease in the expression of Klotho protein compared to the group of intact animals during immunofluorescence analysis. In the group treated with the GABA derivative succicard, there was an improvement in the functional state of the kidneys, accompanied by a significant increase (p≤0,0001) in the area of Klotho-positive material in the epithelium of the convoluted tubules of the kidney in relation to the group of animals with prolonged hyperglycemia without treatment. Conclusion. Prolonged hyperglycemia causes severe renal dysfunction in rats with streptozotocin diabetes: an increase the proteinuria and serum creatinine levels is accompanied by a decrease in the expression of Klotho protein in the kidneys. The GABA derivative succicard with course administration improves kidney function and this effect is accompanied by an increase in the expression of Klotho protein.

Cardioprotective and renoprotective effects of melatonin and vitamin E on fluoride-induced hypertension and renal dysfunction in rats

Cardioprotective and renoprotective effects of melatonin and vitamin E on fluoride-induced hypertension and renal dysfunction in rats

Alleviative effects of pinostrobin against cadmium-induced renal toxicity in rats by reducing oxidative stress, apoptosis, inflammation, and mitochondrial dysfunction.

Cadmium (Cd) is a highly toxic heavy metal that can be found everywhere in the environment and can have harmful effects on both human and animal health. Pinostrobin (PSB) is a bioactive natural flavonoid isolated from Boesenbergia rotunda with several pharmacological properties, such as antiinflammatory, anticancer, antioxidant, and antiviral. This investigation was intended to assess the therapeutic potential of PSB against Cd-induced kidney damage in rats. In total, 48 Sprague Dawley rats were divided into four groups: a control, a Cd (5 mg/kg), a Cd + PSB group (5 mg/kg Cd and 10 mg/kg PSB), and a PSB group (10 mg/kg) that received supplementation for 30 days. Exposure to Cd led to a decrease in the activities of catalase (CAT), glutathione reductase (GSR), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX), whereas levels of reactive oxygen species (ROS) and malondialdehyde (MDA) increased. Cd exposure also caused a substantial increase in urea, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and creatinine levels. Moreover, a noticeable decline was noticed in creatinine clearance. Moreover, Cd exposure considerably increased the levels of inflammatory indices, including interleukin-1b (IL-1b), tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), nuclear factor kappa-B (NF-kB), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) activity. Cd treatment decreased the expression of the antiapoptotic markers (Bcl-2) while increasing the expression of apoptotic markers (Bax and Caspase-3). Furthermore, Cd treatment substantially reduced the TCA cycle enzyme activity, such as alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, and isocitrate dehydrogenase. Moreover, mitochondrial electron transport chain enzymes, succinatedehydrogenase, NADH dehydrogenase, cytochrome c-oxidase, and coenzyme Q-cytochrome reductase activities were also decreased following Cd exposure. PSB administration substantially reduced the mitochondrial membrane potential while inducing significant histological damage. However, PSB treatment significantly reduced Cd-mediated renal damage in rats. Thus, the present investigation discovered that PSB has ameliorative potential against Cd-induced renal dysfunction in rats.

DF-5 COMPOUND DELAYS DEVELOPMENT OF DIABETIC NEPHROPATHY IN RATS

Advanced glycation end-products play an important role in the development of diabetic complications, so slowing down of glycated proteins’ cross-links formation have been suggested as a potential therapeutic option for the treatment of vascular diabetic complications and preventing their progression.The aim of the work was to assess the influence of novel anticrosslinking agent DF-5 on the renal advanced glycation end-products and collagen contents, body weight, blood glucose and glycated hemoglobin levels and the development of early renal disease in streptozotocin-induced diabetic rats.Materials and methods. 40 male Sprague-Dawley rats were used in the study. Two months after inducing diabetes, the study substance was administered intragastrically once a day for 28 days (12.5 mg/kg). Measurements included the assessment of blood glucose and HbA1c levels, the evaluation of the renal function, and the results of histology and immunohistochemical staining of kidneys.Results. A repeated intragastric administration of DF-5 for 30 days significantly reduced the level of HbA1c in the blood, but did not affect the level of fasting blood glucose. DF-5 compound significantly reduced proteinuria and prevented kidney damage in experimental animals by limiting damage of the glomeruli and tubules. It was found that DF-5 inhibits the progression of an early renal dysfunction in rats with streptozotocin-induced diabetic nephropathy. This was associated with a decreased accumulation of advanced glycation end-products in the kidney, accompanied by the improvement of both renal morphology and function.Conclusion. The results obtained provide investigators with additional therapeutic options for the treatment of diabetic nephropathy and possibly other complications of diabetes.

The diminution and modulation role of water-soluble gallic acid-carboxymethyl chitosan conjugates against the induced nephrotoxicity with cisplatin

The toxicity of cisplatin (CDDP) toward the renal tubules and its severe effects on the proximal tubules limits its further use in cancer therapy. The current study was undertaken to evaluate the protective effects of gallic acid-grafted O-carboxymethyl chitosan (GA@CMCS) against nephrotoxicity induced by CDDP in rats. Renal injury was assessed in the GA@CMCS/CDDP-treated rats using kidney injury molecule-1 (KIM-1). Moreover, the levels of reduced glutathione (GSH), malondialdehyde (MDA), and nitric oxide (NO) were measured. The comet assay was performed to measure the DNA damage. The renoprotective activity of GA@CMCS was supported by histo- and immuno-pathological studies of the kidney. GA@CMCS significantly normalized the increases in kidney homogenate of KIM-1, MDA, and NO-induced by CDDP and significantly increased GSH as compared with the CDDP group. GA@CMCS also significantly protects rat kidneys from CDDP-induced histo- and immuno-pathological changes. Both biochemical findings and histo- and immuno-pathological evidence showed the renoprotective potential of GA@CMCS against CDDP-induced oxidative stress, inflammation, and renal dysfunction in rats. In conclusion, GA@CMCS has been shown to mitigate the nephrotoxicity impact of CDDP in cancer therapy.

Ameliorative Impacts of Wheat Germ Oil against Ethanol-Induced Hepatic and Renal Dysfunction in Rats: Involvement of Anti-Inflammatory, Anti-Apoptotic, and Antioxidant Signaling Pathways.

Wheat germ oil (WGO) is a well-known product with anti-inflammatory and antioxidant properties. The current study aimed to investigate the impacts of WGO against ethanol-induced liver and kidney dysfunction at the serum, anti-inflammatory, antioxidants and anti-apoptotic signaling pathways. Rats received saline orally as a negative control or WGO in a dose of 1.5 mL/kg (1400 mg/kg body weight orally) for 15 days. The affected group received ethanol 50% v/v 10 mL/kg (5 g/kg) body weight orally once a day for consecutive 15 days to induce hepatorenal injuries in ethanolic non-treated group. The protective group received WGO daily 1 h before ethanol administration. Serum (1.5 mL) from blood was extracted and examined for the changes in biochemical assessments in serum alkaline phosphatase (ALP), alanine aminotransferase (ALT), bilirubin, serum γ-glutamyl transpeptidase (GGT), total protein, serum albumin, butyrylcholinesterase (BChE), total cholesterol (TC), total triglyceride (TG), urea, creatinine, uric acid, potassium (K+), Beta-2 microglobulin (β2M), malondialdehyde (MDA), catalase (CAT), reduced glutathione (GSH), superoxide dismutase (SOD) and aspartate aminotransferase (AST). Kidney and liver homogenate was used to measure MDA, GSH and catalase activities. Quantitative real time PCR (qRT-PCR) was used to express Nrf2 and HO-1 in liver, and NF-kB and kidney injury molecule (KIM-1) in kidneys, which are correlated with oxidative stress and inflammation. Capase-3 and Bcl2 genes were examined using immunohistochemical analysis in the kidney and liver. Ethanol administration induced significant alteration in examined liver and kidney markers (AST, ALT, GGT, ALP, total proteins, urea, creatinine and uric acid). Moreover, alcohol administration decreased antioxidant activities at serum and hepatorenal tissues (GSH, catalase and SOD), while MDA was increased as a tissue degradation marker. Inflammatory cytokines, together with genes of oxidative stress markers (Nrf2 and HO-1), were all affected. At cellular levels, apoptotic marker caspase-3 was upregulated, while antiapoptotic marker B-cell lymphoma 2 (Bcl2), was down regulated using immunohistochemical analysis. Of interest, pretreatment with WGO improved the side effects induced by ethanol on hepatic, renal biomarkers and reversed its impact on serum and tissue antioxidant parameters. Nrf2/HO-1 were upregulated, while NFk-B and KIM-1 were downregulated using real time PCR. Immune reactivities of caspase-3 and Bcl2 genes were restored in the protective group. In conclusion, WGO ameliorated ethanol-induced hepatic and renal dysfunction at the biochemical, molecular and cellular levels by regulating some mechanisms that controls oxidative stress, apoptosis, inflammation and anti-apoptotic pathways.

Curative Consequences of Rocket Seeds (Eruca Sativa) Extract against Lead Nanoparticles Induced Renal Dysfunction in Rats

Lead nanoparticles (Pb-NPs) are used in different industrial aspects with potential risk in human health. The current work aimed to appreciate the therapeutic rocket seeds extract effect on against renal toxicity stimulated by (Pb-NPs) via estimation of kidney functions and electrolytes with different histological and immunological studies. Pb-NPs were synthesized by biocompatible chemical coprecipitation of Pb2+ and glucose as a reducing agent. These nanoparticles have been characterized using X-ray diffraction (XRD) and scanning electron microscopy (SEM) techniques. Pb-NPs have a relatively cubic shape with diameter about 16 nm. The study was performed on 60 male albino rats distributed into four groups (control, rocket- seeds extract, Pb-NPs, and treated) The results demonstrated the toxic effects of Pb-NPs via the destruction of the renal cell resulted in significant elevations of urea and creatinine concentrations which affected on electrolyte hemostasis. The rocket seed extract administration showed beneficial curative effects against renal toxicity induced by Pb-NPs exposure. Rocket seeds extract administration showed regression of the kidney functions and improvement of electrolytes hemostasis. These result were indicated by histopathological and immunohistochemical analysis

Exogenous glutathione protects against gentamicin-induced acute kidney injury by inhibiting NF-κB pathway, oxidative stress, and apoptosis and regulating PCNA

This study was designed, for the first time, to examine the possible nephroprotective effects of exogenous glutathione (EGSH) (100 mg/kg, intraperitoneally) on gentamicin-induced acute kidney injury (GM-induced AKI). EGSH reduced renal histopathological changes, inflammatory cell infiltration, and improved renal dysfunction in rats with AKI. EGSH ameliorated GM-induced renal oxidative stress by promoting the renal activities of catalase, glutathione peroxidase, and superoxide dismutase and diminishing renal malondialdehyde and serum nitric oxide levels. Interestingly, EGSH inhibited intrinsic apoptosis by downregulating Bax and caspase-3 and upregulating Bcl2 in the kidney of rats with AKI. EGSH decreased GM-induced inflammatory response as reflected by a remarkable decrease in the protein expressions of NF-κB-p65, IL-6, TNF-α, and iNOS and a considerable diminish in myeloperoxidase activity. Finally, EGSH markedly declined proliferative cell nuclear antigen (PCNA) protein expression in the animals with AKI. In summary, EGSH alleviated AKI in rats intoxicated with GM, partially by inhibiting oxidative stress, NF-κB pathway, and intrinsic apoptosis and regulating PCNA.

Oral Treatment with Angiotensin-(1-7) Attenuates the Kidney Injury Induced by Gentamicin in Wistar Rats.

Acute Kidney Injury (AKI), a common disease of the urinary system, can be induced by high doses of gentamicin (GM). The renin-angiotensin system exerts a key role in the progression of the AKI since elevated intrarenal levels of Ang II, and ACE activity is found in this condition. However, it is unknown whether oral administration of angiotensin (Ang)-(1-7), a heptapeptide that evokes opposite effects of Ang II, may attenuate the renal injuries induced by gentamicin. To evaluate the effects of Ang-(1-7) on GM-induced renal dysfunction in rats. AKI was induced by subcutaneous administration of GM (80 mg/Kg) for 5 days. Simultaneously, Ang-(1-7) included in hydroxypropyl β-cyclodextrin (HPβCD) was administered by gavage [46 μg/kg HPβCD + 30 μg/kg Ang-(1-7)]. At the end of the treatment period (sixth day), the rats were housed in metabolic cages for renal function evaluation. Thereafter, blood and kidney samples were collected. Ang-(1-7) attenuated the increase of the plasmatic creatinine and proteinuria caused by GM but did not change the glomerular filtration rate nor tubular necrosis. Ang-(1-7) attenuated the increased urinary flow and the fractional excretion of H2O and potassium observed in GM rats but intensified the elevated excretion of sodium in these animals. Morphological analysis showed that Ang-(1-7) also reduced the tubular vacuolization in kidneys from GM rats. Ang-(1-7) promotes selective beneficial effects in renal injuries induced by GM.

Betaine attenuates sodium arsenite-induced renal dysfunction in rats

Exposure to higher levels of arsenic is a serious threat affecting human health worldwide. We investigated the protective role of betaine (N,N,N-trimethylglycine) against sodium arsenite-induced renal dysfunction in rats. Sodium arsenite (5 mg/kg, oral) was given to rats for 4 weeks to induce nephrotoxicity. Betaine (125 and 250 mg/kg, oral) was administered in rats for 4 weeks along with sodium-arsenite feeding. Arsenic-induced renal dysfunction was demonstrated by measuring serum creatinine, creatinine clearance, urea, uric acid, potassium, fractional excretion of sodium, and microproteinuria. Oxidative stress in rat kidneys was determined by assaying thiobarbituric acid reactive substances, superoxide anion generation, and reduced glutathione levels. Furthermore, hydroxyproline assay was done to assess renal fibrosis in arsenic intoxicated rats. Hematoxylin-eosin and picrosirius red staining revealed pathological alterations in rat kidneys. Renal endothelial nitric oxide synthase (eNOS) expression was determined by immuno-histochemistry. Concurrent administration of betaine abrogated arsenic-induced renal biochemical and histological changes in rats. Betaine treatment significantly attenuated arsenic-induced decrease in renal eNOS expression. In conclusion, betaine is protective against sodium arsenite-induced renal dysfunction, which may be attributed to its anti-oxidant activity and modulation of renal eNOS expression in rat kidneys.

Ameliorative role of inducible nitric oxide synthase inhibitors against sodium arsenite-induced renal and hepatic dysfunction in rats

Arsenic exposure causes immense health distress by increasing risk of cardiovascular abnormalities, diabetes mellitus, neurotoxicity, and nephrotoxicity. The present study explored the role of inducible nitric oxide synthase (iNOS) inhibitors against sodium arsenite-induced renal and hepatic dysfunction in rats. Female Sprague Dawley rats were subjected to arsenic toxicity by administering sodium arsenite (5 mg/kg/day, oral) for 4 weeks. The iNOS inhibitors, S-methylisothiourea (10 mg/kg, i.p.) and aminoguanidine (100 mg/kg, i.p.) were given one hour before sodium arsenite administration in rats for 4 weeks. Sodium arsenite led rise in serum creatinine, urea, uric acid, electrolytes (potassium, fractional excretion of sodium), microproteinuria, and decreased creatinine clearance (p < 0.001) indicated renal dysfunction in rats. Arsenic-intoxication resulted in significant oxidative stress in rat kidneys, which was measured in terms of increase in lipid peroxides, superoxide anion generation and decrease in reduced glutathione (p < 0.001) levels. A threefold increase in renal hydroxyproline level in arsenic intoxicated rats indicated fibrosis. Hematoxylin–eosin staining indicated tubular damage, whereas picrosirius red staining highlighted collagen deposition in rat kidneys. S-methylisothiourea and aminoguanidine improved renal function and attenuated arsenic led renal oxidative stress, fibrosis, and decreased the kidney injury score. Additionally, arsenite-intoxication resulted in significant rise in hepatic parameters (serum aspartate aminotransferase, alanine transferase, alkaline phosphatase, and bilirubin (p < 0.001) along with multi-fold increase in oxidative stress, fibrosis and liver injury score in rats, which was significantly (p < 0.001) attenuated by concurrent administration of iNOS inhibitors). Hence, it is concluded that iNOS inhibitors attenuate sodium arsenite-induced renal and hepatic dysfunction in rats.

Thymoquinone, but Not Metformin, Protects against Gentamicin-Induced Nephrotoxicity and Renal Dysfunction in Rats

Background: Gentamicin (GM) is an antibiotic that is widely used to treat many Gram-negative bacteria, such as those involved in urinary tract infections. However, being nephrotoxic, GM dose adjustment and reno-protective elements must be concurrently administered with GM to minimize kidney damage. Oxidative stress plays a pivotal role in the pathogenesis of GM-induced nephrotoxicity. Thymoquinone (TQ) is a promising therapeutic substance, that is being extensively studied in many diseases, such as diabetes mellitus, cancer, hypertension, and others. The powerful antioxidant properties of TQ may greatly help in minimizing GM nephrotoxicity. Metformin (MF) is a well-known, clinically approved oral hypoglycaemic drug that has many other actions, including antioxidant properties. The aim of this work was to evaluate the possible antioxidant and reno-protective effects of TQ and metformin in GM-induced nephrotoxicity in the same model (rats) at the same time. In addition, we aimed to further understand the effects underlying GM-induced nephrotoxicity. Methods: Twenty male rats were randomly divided into four equal groups: the first group (control) received distilled water; the second group received GM only; the third group received concurrent oral TQ and GM; and the fourth group received concurrent oral MF and GM. After 4 weeks, renal function and histopathology, as well as levels of the oxidative markers glutathione peroxidase-1 (GLPX1), superoxide dismutase (SOD), and malondialdehyde (MDA) in the kidney tissues, were assessed. Results: Compared with the control group, and as expected, the GM-injected rats showed significant biochemical and histological changes denoting renal damage. Compared with GM-injected rats, the concurrent administration of TQ with GM significantly reduced the levels of serum creatinine, serum urea, and tissue MDA and significantly increased the levels of GLPX1 and SOD. Concurrent metformin administration with GM significantly increased the levels of both GLPX1 and SOD and significantly decreased the levels of tissue MDA but had no significant effect on serum creatinine and urea levels. Compared with GM-injected rats, the addition of either TQ or MF resulted in a reduction in endothelial proliferation and mesangial hypercellularity. Conclusions: Both TQ and MF effectively alleviated the oxidative stress in GM-induced nephrotoxicity in rats, with TQ but not MF producing a complete reno-protective effect. Further studies for evaluation of different reno-protective mechanisms of TQ should be conducted.

Isorhynchophylline ameliorates paraquat-induced acute kidney injury by attenuating oxidative stress and mitochondrial damage via regulating toll-interacting expression

Isorhynchophylline (IRN) is an alkaloid with anti-inflammatory and anti-oxidative activities in cardiovascular and brain diseases, but its role in paraquat (PQ)-induced acute kidney injury (AKI) is yet unknown. The model of PQ-induced AKI in rats was established by intraperitoneal injection of PQ (25 mg/kg). We found that the tail vein injection of IRN (4 mg/kg) significantly increased the survival rate of PQ-intoxicated rats. IRN administration alleviated PQ-induced renal injury and renal dysfunction in rats, as evidenced by decreased apoptosis in renal cortex and reduced serum creatinine, serum BUN, and urine NGAL levels. Furthermore, IRN treatment improved the PQ-triggered oxidative stress in renal cortex by increasing the levels of anti-oxidant indicators (SOD activity, GSH/GSSG ratio, levels of Nrf-2, NQO-1, and HO-1 in renal cortex) and decreasing the levels of oxidative stress indexes (ROS and MDA levels in renal cortex). Interestingly, toll-interacting protein (Tollip), a negative regulator of interleukin 1 receptor associated kinase 1 (IRAK1) phosphorylation, was demonstrated to be increased by IRN injection in the renal cortex of PQ-intoxicated rats. In vitro experiments revealed that IRN protected renal tubular epithelial cells against PQ toxicity through suppressing oxidative stress and mitochondrial damage, and these protective effects were reversed by Tollip shRNA. Collectively, the present study demonstrated that IRN ameliorated PQ-induced AKI by attenuating oxidative stress and mitochondrial damage through upregulating Tollip, which provides new insights into the pathogenesis and treatment of PQ poisoning.

Diphenyl diselenide ameliorates diabetic nephropathy in streptozotocin-induced diabetic rats via suppressing oxidative stress and inflammation

Oxidative stress and inflammation are implicated in the occurrence and progression of diabetic nephropathy (DN). Diphenyl diselenide (DPDS) is a stable and simple diaryl diselenide with anti-hyperglycemic, anti-inflammatory, and antioxidant activities. However, the effects of DPDS on DN are still unclear to date. Herein, we aimed to explore whether DPDS could improve renal dysfunction in streptozotocin (STZ)-induced diabetic rats and its underlying mechanisms. STZ-induced DN rats were administered with DPDS (5 or 15 mg/kg) or metformin (200 mg/kg) once daily by intragastric gavage for 12 weeks. DPDS supplementation significantly improved hyperglycemia, glucose intolerance, dyslipidemia, and the renal pathological abnormalities, concurrent with significantly reduced serum levels of creatinine, urea nitrogen, urine volume, and urinary levels of micro-albumin, β2-microglobulin and N-acetyl-glucosaminidase activities. Moreover, DPDS effectively promoted the activities of antioxidant enzymes, and reduced the levels of MDA and pro-inflammatory factors in serum and the kidney. Furthermore, DPDS supplementation activated the renal Nrf2/Keap1 signaling pathway, but attenuated the high phosphorylation levels of NFκB, JNK, p38 and ERK1/2. Altogether, the current study indicated for the first time that DPDS ameliorated STZ-induced renal dysfunction in rats, and its mechanism of action may be attributable to suppressing oxidative stress via activating the renal Nrf2/Keap1 signaling pathway and mitigating inflammation by suppressing the renal NFκB/MAPK signaling pathways, suggesting a potential therapeutic approach for DN.

Protective effect of vitamin E on nickel sulfate-induced renal dysfunction in rats

Introduction: The kidney is a major organ for nickel induced toxicity. Objectives: The purpose of this investigation was to determine the protective impact of vitamin E on nickel sulfate (NiSO4 ) caused kidney dysfunction in rats using biochemical and histopathological approaches. Materials and Methods: Adult male Wistar rats were selected as animal models and randomly divided into four groups (five rats in each group) as follows; group 1. The animals received orally (gavage) 250 mg/kg vitamin E (dissolved in corn oil) 30 minutes before inhalation exposure to1mg NiSO4 /m3 . This experiment was performed for 6 hours daily for 10 consecutive days. Group 2; the rats received by gavage corn oil (vehicle) 30 minutes before inhalation exposure to1mg NiSO4 /m3 . This experiment was performed for 6 hours daily for 10 consecutive days. Group 3; animals of this group were given by gavage 250 mg/kg vitamin E only (without exposure to NiSO4 ) for 10 consecutive days. Group fourth were received by gavage an equal volume of vehicle (corn oil) for 10 consecutive days. All animals were killed 24 hours after the last treatments with sodium pentobarbital. Kidney tissues were removed. One part of the tissues were used for glutathione (GSH) and malondialdehyde (MDA) determination, other parts were fixed and processed for light microscopy. Results: The levels of MDA significantly increased and GSH decreased in rats exposed to NiSO4 in comparison to those in non-exposed rats. Histopathological observations also indicated that NiSO4 induced damage in the kidney. Additionally, administration of vitamin E prior to exposure to NiSO4 markedly decreased renal damage-induced by NiSO4 . Conclusion: The study showed that respiratory inhalation of NiSO4 induced oxidative stress and caused cell damage in rats’ kidney. Vitamin E effectively alleviated Ni-induced nephrotoxicity in rats. These observations suggest that vitamin E may have a protective effect against Ni-induced oxidative stress in the rats’ kidney.

Ameliorative role of bosentan, an endothelin receptor antagonist, against sodium arsenite-induced renal dysfunction in rats.

Arsenic exposure is well documented to cause serious health hazards, such as cardiovascular abnormalities, neurotoxicity and nephrotoxicity. In the present study, we intended to explore the role of bosentan, an endothelial receptor antagonist, against sodium arsenite-induced nephrotoxicity and hepatotoxicity in rats. Sodium arsenite (5 mg/kg, oral) was administered for 4 weeks to induce renal dysfunction in rats. Sodium arsenite intoxicated rats were treated with bosentan (50 and 100 mg/kg, oral) for 4 weeks. Arsenic led renal damage was demonstrated by significant increase in serum creatinine, urea, uric acid, potassium, fractional excretion of sodium, microproteinuria and decreased creatinine clearance in rats. Sodium arsenite resulted in marked oxidative stress in rat kidneys as indicated by profound increase in lipid peroxides, and superoxide anion generation alongwith decrease in reduced glutathione levels. Hydroxyproline assay highlighted arsenic-induced renal fibrosis in rats. Hematoxylin-eosin staining indicated glomerular and tubular changes in rat kidneys. Picrosirius red staining highlighted collagen deposition in renal tissues of arsenic treated rats. Immunohistological results demonstrated the reduction of renal eNOS expression in arsenic treated rats. Notably, treatment with bosentan attenuated arsenic-induced renal damage and resisted arsenic-led reduction in renal eNOS expression. In addition, sodium arsenite-induced alteration in hepatic parameters (serum aspartate aminotransferase, alanine transferase, alkaline phosphatase, bilirubin), oxidative stress and histological changes were abrogated by bosentan treatment in rats. Hence, we conclude that bosentan treatment attenuated sodium arsenite-induced oxidative stress, fibrosis and reduction in renal eNOS expression in rat kidneys. Moreover, bosentan abrogated arsenic led hepatic changes in rats.

Effect of imidazoline-1 receptor agonists on renal dysfunction in rats associated with chronic, sequential fructose and ethanol administration.

Insulin resistance and chronic alcoholism are risk factors for renal dysfunction. This study investigated the therapeutic effects of two imidazoline-1 receptor (I1R) agonists on renal dysfunction in rats after chronic, sequential fructose and ethanol administration. Daily drinking water was supplemented with fructose (10%, w/v) for 12weeks and then with ethanol (20%, v/v) for another 8weeks. Rats were treated with rilmenidine and clonidine in the last two weeks of the study. Blood glucose and serum insulin (sIns) levels, lipid profiles, kidney function and renal histopathology were evaluated at the end of the experiment. Additionally, renal gene expression of nischarin, phosphatidylcholine-specific phospholipase C (PC-PLC) and prostaglandin E2 (PGE2) were measured. Renal levels of superoxide dismutase (SOD), malondialdehyde (MDA), myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS) and total NO (tNO) were detected, and we determined the relative renal gene expression levels of alpha smooth muscle actin (α-SMA), hydroxyproline, interleukin 10 (IL-10), tumour necrosis factor alpha (TNF-α) and caspase-3. The results showed significant deterioration of blood glucose, sIns, lipid profiles, kidney function and renal histopathology in fructose/ethanol-fed rats. Additionally, markers of inflammation, fibrosis, apoptosis and oxidative stress were upregulated. The administration of rilmenidine or clonidine significantly improved blood glucose and sIns levels and reduced renal dysfunction. Our work showed that chronic, sequential fructose and ethanol administration induced fasting hyperglycaemia and renal impairment, and these effects were ameliorated by I1R agonists.

490-P: Administration of AAV-Containing Glyoxalase-I Attenuated Nephropathy in Rats with Chronic Diabetes

Supra-physiologic flux/production of methylglyoxal (MG) has emerged as an underlying cause of nephropathy in chronic type 1 diabetes mellitus (T1DM). This increased MG arises in part from a reduction in expression of its detoxifying enzyme, glyoxalase-I (Glo-I). Adeno-associated virus (AAV)-mediated gene transfer has materialized as a promising strategy to increase expression of deficit proteins in disease states. Here we compared the efficacies of AAV2/9 containing Glo-I driven by two promoters, endothelin-1 (AAV2/9-Endo-Glo-I) and cytomegalovirus (AAV2/9-CMV-GloI) to attenuate nephropathy in T1DM rat. After eight weeks of T1DM, urine production increased 4-fold, urine norepinephrine increased 2.5-fold, serum creatinine increased 4-fold, creatinine clearance decreased 4-fold, BUN increased 5-fold, and proteinuria increased 8-fold. Renal Glo-I protein was 50% lower, MG was 2.5-fold higher, and extravasation of albumin from peritubular and glomerular capillaries and fibrosis were prominent. TNF-α and NF-κB (p65) phosphorylation were increased 3-4 folds. A single bolus injection of AAV/2/9 Glo-I and AAV2/9-Glo-I (1.7×1012 viron particles/kg) ten days after T1DM onset blunted increases in water consumption and urine assayed eight weeks later. AAV2/9-Glo-I also attenuated increases in norepinephrine, creatinine, BUN, proteinuria, albumin extravasation from renal microvessels, fibrosis, MG, TNF-α, NF-κB, activation and increased creatinine clearance rate. The magnitudes of the effects were higher in AAV2/9-Endo-Glo-I injected rats in part to higher expression of Glo-I in tubules and reduced expression of the MG-synthesizing enzyme vascular adhesion protein-1 within glomeruli. These new data demonstrate that intravenous administration of AAV2/9-containing Glo-I after the onset of T1DM attenuated renal dysfunction in rats via multiple mechanisms involving reductions in sympatho-excitation, inflammation, microvascular leakage and fibrosis. Disclosure K. Bidasee: None. F.A. Alomar: None. Funding National Institutes of Health (P30GM103335); University of Nebraska Medical Center (GTRP 1053); UNeMed

Serological, histopathologic and scintigraphic assessment of Hemiscorpius lepturus effects on renal dysfunction in rats

Serological, histopathologic and scintigraphic assessment of Hemiscorpius lepturus effects on renal dysfunction in rats