Gentamicin-induced Renal Injury Research Articles

Lysosomal membrane stabilization by imipramine attenuates gentamicin-induced renal injury: Enhanced LAMP2 expression, down-regulation of cytoplasmic cathepsin D and tBid/cytochrome c/cleaved caspase-3 apoptotic signaling

Nephrotoxicity is a serious complication commonly encountered with gentamicin (GTM) treatment. Permeabilization of lysosomes with subsequent cytoplasmic release of GTM and cathepsins is considered a crucial issue in progression of GTM toxicity. This study was designed to evaluate the prospective defensive effect of lysosomal membrane stabilization by imipramine (IMP) against GTM nephrotoxicity in rats. GTM (30 mg/kg/h) was intraperitoneally administered over 4 h daily (120 mg/kg/day) for 7 days. IMP (30 mg/kg/day) was orally administered for 14 days; starting 7 days before and then concurrently with GTM. On 15th day, samples (urine, blood, kidney) were collected to estimate biomarkers of kidney function, lysosomal stability, apoptosis, and inflammation. IMP administration to GTM-treated rats ameliorated the disruption in lysosomal membrane stability induced by GTM. That was evidenced by enhanced renal protein expressions of LAMP2 and PI3K, but reduced cathepsin D cytoplasmic expression in kidney sections. Besides, IMP guarded against apoptosis in GTM-treated rats by down-regulation of the pro-apoptotic (tBid, Bax, cytochrome c) and the effector cleaved caspase-3 expressions, while the anti-apoptotic Bcl-2 expression was enhanced. Additionally, the inflammatory cascade p38 MAPK/NF-κB/TNF-α was attenuated in GTM + IMP group along with marked improvement in kidney function biomarkers, compared to GTM group. These findings were supported by the obvious improvement in histological architecture. Furthermore, in vitro enhancement of the antibacterial activity of GTM by IMP confers an additional benefit to their combination. Conclusively, lysosomal membrane stabilization by IMP with subsequent suppression of tBid/cytochrome c/cleaved caspase-3 apoptotic signaling could be a promising protective strategy against GTM nephrotoxicity.

Shikonin Alleviates Gentamicin-Induced Renal Injury in Rats by Targeting Renal Endocytosis, SIRT1/Nrf2/HO-1, TLR-4/NF-κB/MAPK, and PI3K/Akt Cascades.

Gentamicin causes kidney injury due to its accumulation in proximal tubule epithelial cells via the megalin/cubilin/CLC-5 complex. Recently, shikonin has been shown to have potential anti-inflammatory, antioxidant, antimicrobial, and chloride channel-inhibiting effects. The current study investigated the alleviation of gentamicin-induced renal injury by shikonin while preserving its bactericidal effect. Nine-week-old Wistar rats were administered 6.25, 12.5, and 25 mg/kg/day shikonin orally, one hour after the i.p. injection of 100 mg/kg/day gentamicin for seven days. Shikonin significantly and dose-dependently alleviated gentamicin-induced renal injury, as revealed by restoring normal kidney function and histological architecture. Furthermore, shikonin restored renal endocytic function, as indicated by suppressing the elevated renal megalin, cubilin, and CLC-5 and enhancing the reduced NHE3 levels and mRNA expressions induced by gentamicin. These potentials could be attributed to the modulation of the renal SIRT1/Nrf2/HO-1, TLR-4/NF-κB/MAPK, and PI3K/Akt cascades, which enhanced the renal antioxidant system and suppressed renal inflammation and apoptosis, as indicated by enhancements of SIRT1, Nrf2, HO-1, GSH, SOD, TAC, Iκb-α, Bcl-2, PI3K, and Akt levels and mRNA expressions, with reduction of TLR-4, NF-κB, MAPK, IL-1β, TNF-α, MDA, iNOS, NO, cytochrome c, caspase-3, Bax levels, and Bax/Bcl-2 ratio. Therefore, shikonin is a promising therapeutic agent for alleviating gentamicin-induced renal injury.

Oxymatrine Alleviates Gentamicin-Induced Renal Injury in Rats.

Gentamicin is an aminoglycoside antibiotic commonly used to treat Gram-negative bacterial infections that possesses considerable nephrotoxicity. Oxymatrine is a phytochemical with the ability to counter gentamicin toxicity. We investigated the effects and protective mechanism of oxymatrine in rats. The experimental groups were as follows: Control, Oxymatrine only group (100 mg/kg/d), Gentamicin only group (100 mg/kg/d), Gentamicin (100 mg/kg/d) plus Oxymatrine (100 mg/kg/d) group (n = 10). All rats were treated for seven continuous days. The results indicated that oxymatrine alleviated gentamicin-induced kidney injury, and decreased rats’ kidney indices and NAG (N-acetyl-beta-d-glucosaminidase), BUN (blood urea nitrogen) and CRE (creatine) serum levels. The oxymatrine-treated group sustained less histological damage. Oxymatrine also relived gentamicin-induced oxidative and nitrative stress, indicated by the increased SOD (superoxidase dismutase), GSH (glutathione) and CAT (catalase) activities and decreased MDA (malondialdehyde), iNOS (inducible nitric oxide synthase) and NO (nitric oxide) levels. Caspase-9 and -3 activities were also decreased in the oxymatrine-treated group. Oxymatrine exhibited a potent anti-inflammatory effect on gentamicin-induced kidney injury, down-regulated the Bcl-2ax and NF-κB mRNAs, and upregulated Bcl-2, HO-1 and Nrf2 mRNAs in the kidney tissue. Our investigation revealed the renal protective effect of oxymatrine in gentamicin-induced kidney injury for the first time. The effect was achieved through activation of the Nrf2/HO-1 pathways. The study underlines the potential clinical application of oxymatrine as a renal protectant agent for gentamicin therapy.

Chemical Composition and Valorization of Broccoli Leaf By-Products (Brassica oleracea L. Variety: Italica) to Ameliorate Reno-Hepatic Toxicity Induced by Gentamicin in Rats

Broccoli (Brassica oleracea) is reported to possess antioxidant activity that could potentially prevent oxidative damage to tissues caused by many diseases. In the present study, we investigated the preventive effect of broccoli leaf by-product extract (BL) on gentamicin-induced renal and hepatic injury by measuring tissue antioxidant activities and morphological apoptotic changes. Broccoli leaf was thoroughly extracted with 70% methanol to yield the total methanol extract (TME). The total phenolic content (TPC) was determined. Thirty male rats were divided into five groups (six animals/group). Group I received phosphate-buffered saline orally, while group II was treated with gentamicin (100 mg/kg i.p. intraperitoneal) for ten days. Group III and group IV animals were given BL (200 mg/kg and 400 mg/kg, respectively) plus gentamicin treatment. Group V received L-cysteine (1 mmole/kg) plus gentamicin. Antioxidant and biochemical parameters, such as transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP), creatinine, and urea, and mRNA expression levels of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and nuclear factor kappa B (NFkB) were determined in various groups, along with the quantification of inflammatory and apoptotic cells in hepatic and renal tissues. Malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) levels were determined in liver and renal samples. Histopathological studies of the liver and kidneys were also carried out. The TME was subjected to various and repeated techniques of chromatography to yield caffeic acid, gallic acid, and methyl gallate. The TPC was 6.47 mg Gallic Acid Equivalent/g of dry extract. Gentamicin increased the levels of serum AST, ALT, ALP, creatinine, and urea. The MDA and GSH contents and theactivity levels of the antioxidant enzyme SOD decreased in liver and kidney samples with gentamicin administration. BL administration dose-dependently prevented the alteration in biochemical parameters and was supported by low levels of tubular and glomerular injuries induced by gentamicin. This study valorizes the potential of BL as a preventive candidate in cases of gentamicin-induced liver and kidney toxicity and recommends further clinical studies using BL to validate its utilization for human consumption and as a source of phenolics for nutraceutical and pharmaceutical purposes.

L-cysteine protective effects against platelet disaggregation and echinocyte occurrence in gentamicin-induced kidney injury.

Gentamicin (GM) is an aminoglycoside antibiotic that induces nephrotoxicity. GM also causes necrosis of cells in the renal proximal tubules, resulting in acute tubular necrosis, followed by acute renal failure. Morphological alteration of blood cells, leukocytes and platelets count, as well as biochemical effects of L-cysteine (Cys) and antibiotic gentamicin, in clinically healthy male Wistar rats, were studied. Rats were divided into four groups: control (injected with 0.9% saline i.p.), GM (80mg/kg b.w.; gentamicin injected i.p.), Cys-GM (100mg/kg b.w.; L-cysteine and 80mg/kg b.w. gentamicin injected i.p.), and Cys-GM-Cys (administered double dosage of 100mg/kg b.w. L-cysteine and 80mg/kg b.w. gentamicin i.p.). Biochemical and hematological analyses were performed on blood samples taken six days after treatments. Total proteins, albumin concentration and A/G ratio were significantly lower in experimental groups. Cholesterol, triglycerides, urea, and creatinine concentrations were significantly higher in relation to control. GM-induced lymphocytopenia, thrombocytopenia and neutrophilia. Echinocytosis and platelet disaggregation were found in all GM-treated animals. GM caused renal injury which indirectly led to erythrocyte abnormalities, changes in platelet aggregation, decreased protein fractions, and increased lipid and nitrogen components. The results suggest that GM-induced renal injury leads to significant biochemical changes in blood plasma, erythrocyte membrane impairment which can consequently cause anemia. Therefore, Cys might represent a novel therapeutic tool in the prevention and treatment of gentamicin-induced renal injury and blood cell disorders.

Date palm seed extract and herbal mixture mitigate gentamicin-induced renal injury in mice: Role of Protease-activated receptors (PARs) and Retinoid X receptor alpha (RXR-α)

Introduction: Gentamicin (Gen) causes renal toxicity by inhibiting protein synthesis in kidney cells, causing proximal tubule cell necrosis and renal failure. Herein, we examined the nephroprotective effect of date palm seed extract (DPSE) and one herbal mixture (HM; composed of Tribulus terrestris, Aerva lanata, Andrographis paniculata, and Raphanus sativus) against Gen-induced renal toxicity in mice with special reference to the possible role of retinoid X receptor alpha (RXR-α) and protease-activated receptor 2 (PAR-2) in this effect. Methods: Thirty-two male Balb/c mice divided randomly into four groups were either treated with saline, Gen (225 mg/kg/i.p., daily from day 3 to day 10), Gen (225 mg/kg i.p.) daily from day 3 to day 10 and DPSE (100 mg/kg/p.o.) daily for 10 days, or Gen (225 mg/kg i.p.) daily from day 3 to day 10 and HM (100 mg/kg/p.o., daily for 10 days). Mice were sacrificed 24 hours after the last dose administration, and kidney tissues were dissected out, weighed, and subjected to histological, immunofluorescence, and biochemical assays. Results: The Gen-induced renal toxicity group demonstrated a significant decrease in RXR-α and a significant increase in PAR-2 protein expression. Treatment with DPSE or HM significantly improved Gen-induced effects on serum creatinine, blood urea nitrogen (BUN), white blood cells (WBCs), platelets, RXR-α extracellular matrix deposition, and PAR-2. Conclusion: The present study stated the nephroprotective effects of DPSE and HM and revealed, for the first time, the involvement of retinoid receptors and PAR-2 in Gen-induced renal toxicity as well as in the protective effects of the two tested natural products.

Evaluation of Renal Biomarkers, Including Symmetric Dimethylarginine, following Gentamicin-Induced Proximal Tubular Injury in the Rat.

Symmetric dimethylarginine (SDMA) is an excretory renal function biomarker shown to correlate well with glomerular filtration rate in dogs, cats, humans, and rats. The objectives of this study were to determine utility of serum SDMA as a renal biomarker in a rat model of gentamicin-induced renal injury and to provide validation of a commercially available SDMA immunoassay for rat serum. Rats were randomly assigned to one of three dose levels of gentamicin (20, 50, or 100 mg/kg) or a vehicle control group and dosed once daily by subcutaneous injection for either four or ten days. Serum and urine renal biomarker evaluation, including serum SDMA, hematologic and serum biochemical analysis, urinalysis, and histologic examination of kidney, were performed. Before biologic validation, analytic validation of the SDMA immunoassay for rat serum was performed, including assessment of assay accuracy, precision, analytical sensitivity, linearity, analyte stability, and interference testing. Among markers of excretory renal function, SDMA and serum creatinine increased earliest and at the lowest gentamicin concentrations and were significantly increased in both the 50- and 100- mg/kg dose levels in the four- and ten-dose treatment groups compared with controls. Time- and dose-dependent increases were noted for all urinary biomarkers investigated in this study, with microalbumin being most responsive and osteopontin least responsive for detection of gentamicin-induced injury across dose levels and schedules investigated. The SDMA immunoassay met all set quality requirements assessed in analytical validation. This study is the first to investigate performance of serum SDMA compared with other excretory renal function markers in a rat gentamicin acute toxicity model. In this study, serum SDMA was an earlier biomarker for detection of gentamicin-induced toxicity than serum cystatin C, BUN, and creatinine clearance. The SDMA immunoassay provides a reliable commercially available assay for future renal investigations in rat models.

A histopathological study on the effects of atorvastatin against gentamicin-induced renal injury

Introduction: Gentamicin is an aminoglycoside antibiotic that is widely administered to treat infections caused by gram-negative bacteria. Gentamicin may cause renal injury in patients after seven days of administration. Atorvastatin is a cholesterol-lowering statin that acts through the mevalonate pathway. Objectives: In this study, we investigated the histopathological effects of atorvastatin against gentamicin-induced renal injury. Materials and Methods: Twenty male Wistar rats were randomly assigned into five groups and treated as the following; group 1 (normal group, no drug), group 2 [gentamicin group, daily 80 mg/kg, intra-peritoneal (i.p.) for 7 days], groups 3 to 5 (gentamicin 80 mg/kg + atorvastatin at doses of 5, 25 and 75 mg/kg, respectively). Kidney sections were examined for histopathological parameters including vacuolization of the kidney tubular cells, degeneration, necrosis, flattening of the tubular cells and debris in the tubular lumen. Results: Compared to the normal group, gentamicin significantly exacerbated the histopathological parameters. Treatment with atorvastatin significantly decreased vacuolization, degeneration, necrosis and debris in the nephrotoxic rats. Conclusion: The findings of this research indicated that atorvastatin therapy can ameliorate histopathological renal injury following gentamicin injection.

Protective Effect of Polyherbal Extract on Gentamicin-Induced Renal Injury in Wistar Rats

Protective Effect of Polyherbal Extract on Gentamicin-Induced Renal Injury in Wistar Rats

Impact of Human Umbilical Cord Blood Mononuclear Cells on Gentamicin-Induced Renal Injury and Genotoxicity in Rats.

Background: Acute kidney injury (AKI), also known as acute renal failure (ARF), has received considerable critical attention in recent years. Gentamicin (GM) is an antibiotic whose prolonged use results in AKI with a high mortality rate.Methods: Fifty adult female albino rats weighing 150–200 g were used. The animals were divided into five groups: the first group was the normal healthy control one, the second group received only 1 × 106 HUCB mononuclear cells (MNCs)/rat by intravenous (iv) injection, the third diseased group was given GM 100 mg/kg for 10 consecutive days by intraperitoneal injections, the fourth preventive group received 1 × 106 HUCB MNCs/rat by iv injection 24 h before gentamicin treatment, and the fifth treated group received 1 × 106 HUCB MNCs/rat by iv injection 24 h after gentamicin treatment. After 1 week of treatment, blood samples were collected, and kidneys were removed for histopathological examination.Results: Rats treated with HUCB MNCs in the treated group had a significant decrease in renal damage, low levels of biomarkers for nephrotoxicities such as serum creatinine and blood urea nitrogen, and low chromosomal aberrations compared to the diseased third group. The gene expression of KIM-1 and NGAL was decreased in response to HUCB treatment.Conclusions: HUCB MNCs have a curative effect against AKI and gentamicin-induced genotoxicity owing to their regenerative property.

Protective Effects of Valsartan on Gentamicin Induced Tubular Injury through Down Regulation of Urinary N-Acetyl-?-D-Glucosaminidase in Rats

Urinary N-acetyl-β-D-glucosaminidase is a marker of early tubular damage. Therefore, the current study was to investigate effects and its underling mechanisms of valsartan on gentamicin induced renal tubular injury through urinary N-acetyl-β-D-glucosaminidase parameter variety in rats. Animals were divided into four groups consisting of 12 rats each. The study lasted for 10 d. Rats were treated in two batches on the 6th and 11th d of the experiment, with 6 rats in each group. Control group rats were administered with distilled water (10 ml/kg) daily via an intragastric gavage; gentamicin group rats were given gentamicin 100 mg/kg/d intraperitoneally; valsartan (10 mg/kg/d, intragastric gavage) +gentamicin group; valsartan (20 mg/kg/d, intragastric gavage) +gentamicin group. Rats treated with gentamicin showed significant elevation in the activity and expression of urinary N-acetyl-β-D-glucosaminidase as compared with the control group; the activities of superoxide dismutase, glutathione peroxidase and catalase were lower while malondialdehyde was higher in kidney tissues; urinary protein content was not changed; serum creatinine and blood urea nitrogen were increased. Moreover, pathological damage of the renal tubules was serious in gentamicin treated rats. Valsartan significantly inhibited activity and expression of urinary N-acetyl-β-D-glucosaminidase in a dose dependent manner; dramatically increased superoxide dismutase, glutathione peroxidase and catalase activities and markedly decreased malondialdehyde levels in kidney tissues; renal tubular structural damages were also effectively ameliorated by valsartan. These results show that changes of urinary N-acetyl-β-Dglucosaminidase levels can reflect the extent of renal tubular injury, that valsartan has protective role on gentamicin-induced renal tubular injury by down-regulation urinary N-acetyl-β-D-glucosaminidase, and its down-regulation urinary N-acetyl-β-D-glucosaminidase effect may be due to its antioxidant properties in kidney tissues.

Nephroprotective Effect of Cilastatin against Gentamicin-Induced Renal Injury In Vitro and In Vivo without Altering Its Bactericidal Efficiency.

Gentamicin is a used antibiotic that causes nephrotoxicity in 10–20% of treatment periods, which limits its use considerably. Our results have shown that cilastatin may be a promising therapeutic alternative in toxin-induced acute kidney injury (AKI). Here, we investigated its potential use as a nephroprotector against gentamicin-induced AKI in vitro and in vivo. Porcine renal cells and rats were treated with gentamicin and/or cilastatin. In vivo nephrotoxicity was analyzed by measuring biochemical markers and renal morphology. Different apoptotic, oxidative and inflammatory parameters were studied at cellular and systemic levels. Megalin, mainly responsible for the entry of gentamicin into the cells, was also analyzed. Results show that cilastatin protects cells from gentamicin-induced AKI. Cilastatin decreased creatinine, BUN, kidney injury molecule-1 (KIM-1) and severe morphological changes previously increased by gentamicin in rats. The interference of cilastatin with lipid rafts cycling leads to decreased expression of megalin, and therefore gentamicin uptake and myeloid bodies, resulting in a decrease of apoptotic, oxidative and inflammatory events. Moreover, cilastatin did not prevent bacterial death by gentamicin. Cilastatin reduced gentamicin-induced AKI by preventing key steps in the amplification of the damage, which is associated to the disruption of megalin-gentamicin endocytosis. Therefore, cilastatin might represent a novel therapeutic tool in the prevention and treatment of gentamicin-induced AKI in the clinical setting.

Cross organelle stress response disruption promotes gentamicin-induced proteotoxicity

Gentamicin is a nephrotoxic antibiotic that causes acute kidney injury (AKI) primarily by targeting the proximal tubule epithelial cell. The development of an effective therapy for gentamicin-induced renal cell injury is limited by incomplete mechanistic insight. To address this challenge, we propose that RNAi signal pathway screening could identify a unifying mechanism of gentamicin-induced cell injury and suggest a therapeutic strategy to ameliorate it. Computational analysis of RNAi signal screens in gentamicin-exposed human proximal tubule cells suggested the cross-organelle stress response (CORE), the unfolded protein response (UPR), and cell chaperones as key targets of gentamicin-induced injury. To test this hypothesis, we assessed the effect of gentamicin on the CORE, UPR, and cell chaperone function, and tested the therapeutic efficacy of enhancing cell chaperone content. Early gentamicin exposure disrupted the CORE, evidenced by a rise in the ATP:ADP ratio, mitochondrial-specific H2O2 accumulation, Drp-1-mediated mitochondrial fragmentation, and endoplasmic reticulum–mitochondrial dissociation. CORE disruption preceded measurable increases in whole-cell oxidative stress, misfolded protein content, transcriptional UPR activation, and its untoward downstream effects: CHOP expression, PARP cleavage, and cell death. Geranylgeranylacetone, a therapeutic that increases cell chaperone content, prevented mitochondrial H2O2 accumulation, preserved the CORE, reduced the burden of misfolded proteins and CHOP expression, and significantly improved survival in gentamicin-exposed cells. We identify CORE disruption as an early and remediable cause of gentamicin proteotoxicity that precedes downstream UPR activation and cell death. Preserving the CORE significantly improves renal cell survival likely by reducing organelle-specific proteotoxicity during gentamicin exposure.

Potential Nephroprotectice Effect of Curcumin against Gentamicin Induced Nephrotoxicity : An Experimental Study In Rats

Background: Nephrotoxicity is a serious & common side effect of aminoglycoside and is induced by generation of reactive oxygen species. Emerging evidence reveals that curcumin possesses antioxidant activity, therefore, this research was undertaken to evaluate the potential protective effects of curcumin in amiloration of nephrotoxicity induced by gentamicin in male rats.Materials and Methods:Eighteen male Spraque-Dawley rats were included in this study. They were divided randomly into three equal groups (six rats each). Groups I (Control) received only normal saline i.p, Groups II (GN) received gentamicin (100 mg/kg/day), Group III (GN+CUR) received a combination treatment gentamicin (100 mg/kg/day, i.p) & curcumin (200 mg/kg/day p.o). The duration of treatment was eight days and at the end of the study, animals were sacrificed and the blood sample was collected for assessment of renal function, blood urea & serum creatinine. Both kidneys were removed and prepared for a histopathology examination.Results: blood urea and creatinine were significantly higher (P < .05) in gentamycin treated group (group II) as compared to the control group (group I). However, the levels of these parameters in group 3 (co-treatment of gentamicin and curcumin) were significantly lower than those in group 2 (P < .05). Further, the histological score of renal damage was higher in the gentamicin group than in the control group. Combination treatment of curcumin and gentamicin (groupIII) significantly attenuated the histopathological damage.Conclusion: Curcumin attenuated gentamicin-induced renal injury in rats’ models.

Effects of benfotiamine and coenzyme Q10 on kidney damage induced gentamicin.

Gentamicin (GM) is an effective antibiotic against severe infection but has limitations related to nephrotoxicity. In this study, we investigated whether benfotiamine (BFT) and coenzyme Q10 (CoQ10), could ameliorate the nephrotoxic effect of GM in rats. Rats were divided into five groups. Group 1 and 2 served as control and sham respectively, Group 3 as GM group, Group 4 as GM+CoQ10 and Group 5 as GM+BFT for 8days. At the end of the study, all rats were euthanized by cervical decapitation and then blood samples and kidneys were collected for further analysis. Serum urea, creatinine, cytokine TNF-a, oxidant and antioxidant parameters, as well as histopathological examination of kidney tissues were assessed. Gentamicin administration caused a severe nephrotoxicity which was evidenced by an elevated serum creatinine, urea and KIM-1 level as compared with the controls. Moreover, a significant increase in serum malondialdehyde, reduced glutathione. Histopathological examination of renal tissue in gentamisin administered group, there were extremly pronounced necrotic tubules in the renal cortex and hyalen cast accumulation in the medullar tubuli. BFT given to GM rats reduced these nephrotoxicity parameters. Serum creatinine, urea, and KIM-1 were almost normalized in the GM+BFT group. Benfotiamin treatment was significantly decreased necrotic tubuli and hyalen deposition in gentamisin plus benfotiamin group. CoQ10 given to GM rats did not cause any statistically significant alterations in these nephrotoxicity parameters when compared with GM group but histopathological examination of renal tissue in GM+CoQ10 administered group, CoQ10 treatment was decreased necrotic tubuli rate and hyalen accumulation in tubuli. The results from our study indicate that BFT supplement attenuates gentamicin-induced renal injury via the amelioration of oxidative stress and inflammation of renal tubular cells.

ASCORBIC ACID;

Objectives: Investigating the Renoprotective effects of Ascorbic acid ingentamicin induced renal injury (GIRI) in male Wistar rats. Study design: Experimental study.Place and Duration: Animal house of Al-Tibri from September 2016 to December 2016.Methodology: 60 male Wistar rats were selected by non-probability purposive sampling,and were divided into three groups; Group A- control, Group B- Gentamicin induced renalinjury (GIRI) (70 mg/kg/bwt i.m) daily , and Group C- GIRI + AA (Ascorbic acid - 0.2 mg/kg/bwt) daily. Cardiac puncture was performed by a Disposable Syringe for blood sampling.Sera were used for biochemical testing. Renal tissue was stained with H & E for histologicalexamination. Statistix 8.1 software (USA) was used for data analysis at P≤ 0.05. Results:Blood urea and serum creatinine were elevated in the group B (GIRI) compared to GIRI+AAand the controls (P=0.0001). Serum superoxide dismutase, glutathione peroxidase, andcatalase were low in GIRI compared to GIRI+AA and control groups. Renal tissue in ascorbicacid treated rats showed improved tissue architecture. Conclusion: It is concluded that theAscorbic acid exerts Renoprotective effects in gentamicin induced renal injury in rat model.

English

Objectives: Investigating the Renoprotective effects of Ascorbic acid ingentamicin induced renal injury (GIRI) in male Wistar rats. Study design: Experimental study.Place and Duration: Animal house of Al-Tibri from September 2016 to December 2016.Methodology: 60 male Wistar rats were selected by non-probability purposive sampling,and were divided into three groups; Group A- control, Group B- Gentamicin induced renalinjury (GIRI) (70 mg/kg/bwt i.m) daily , and Group C- GIRI + AA (Ascorbic acid - 0.2 mg/kg/bwt) daily. Cardiac puncture was performed by a Disposable Syringe for blood sampling.Sera were used for biochemical testing. Renal tissue was stained with H & E for histologicalexamination. Statistix 8.1 software (USA) was used for data analysis at P≤ 0.05. Results:Blood urea and serum creatinine were elevated in the group B (GIRI) compared to GIRI+AAand the controls (P=0.0001). Serum superoxide dismutase, glutathione peroxidase, andcatalase were low in GIRI compared to GIRI+AA and control groups. Renal tissue in ascorbicacid treated rats showed improved tissue architecture. Conclusion: It is concluded that theAscorbic acid exerts Renoprotective effects in gentamicin induced renal injury in rat model.

MiR-21 is required for efficient kidney regeneration in fish.

BackgroundAcute kidney injury in mammals, which is caused by cardiovascular diseases or the administration of antibiotics with nephrotoxic side-effects is a life-threatening disease, since loss of nephrons is irreversible in mammals. In contrast, fish are able to generate new nephrons even in adulthood and thus provide a good model to study renal tubular regeneration.ResultsHere, we investigated the early response after gentamicin-induced renal injury, using the short-lived killifish Nothobranchius furzeri. A set of microRNAs was differentially expressed after renal damage, among them miR-21, which was up-regulated. A locked nucleic acid-modified antimiR-21 efficiently knocked down miR-21 activity and caused a lag in the proliferative response, enhanced apoptosis and an overall delay in regeneration. Transcriptome profiling identified apoptosis as a process that was significantly affected upon antimiR-21 administration. Together with functional data this suggests that miR-21 acts as a pro-proliferative and anti-apoptotic factor in the context of kidney regeneration in fish. Possible downstream candidate genes that mediate its effect on proliferation and apoptosis include igfbp3 and fosl1, among other genes.ConclusionIn summary, our findings extend the role of miR-21 in the kidney. For the first time we show its functional involvement in regeneration indicating that fast proliferation and reduced apoptosis are important for efficient renal tubular regeneration.Electronic supplementary materialThe online version of this article (doi:10.1186/s12861-015-0089-2) contains supplementary material, which is available to authorized users.

Flavocoxid attenuates gentamicin-induced nephrotoxicity in rats.

Gentamicin is a widely used antibiotic against serious and life-threatening infections; however, its usefulness is limited by the development of nephrotoxicity. The present study was designed to determine whether flavocoxid has a protective effect against gentamicin-induced nephrotoxicity in rats. For this purpose, we quantitatively evaluated gentamicin-induced renal structural and functional alterations using histopathological and biochemical approaches. Furthermore, the effect of flavocoxid on gentamicin induced hypersensitivity of urinary bladder rings to acetylcholine (ACh) was determined. Twenty-four male Wistar albino rats were randomly divided into three groups, namely control, gentamicin (100mg/kg, i.p.) and gentamicin plus flavocoxid (20mg/kg, orally). At the end of the study, all rats were sacrificed and then blood, urine samples and kidneys were collected for further analysis. Gentamicin administration caused a severe nephrotoxicity which was evidenced by an elevated renal somatic index (RSI), serum creatinine, blood urea nitrogen, serum lactate dehydrogenase, and protein in urine with a concomitant reduction in serum albumin and normalized creatinine clearance value as compared with the controls. Moreover, a significant increase in renal contents of malondialdehyde, myeloperoxidase, and tumor necrosis factor-alpha with a significant decrease in renal reduced glutathione and superoxide dismutase activities was detected upon gentamicin administration together with increasing the sensitivity of isolated urinary bladder rings to ACh. Exposure to gentamicin induced necrosis of renal tubular epithelial cells. Flavocoxid protected kidney tissue against the oxidative damage and the nephrotoxic effect caused by gentamicin treatment. In addition, flavocoxid significantly reduced the responses of isolated bladder rings to ACh. The results from our study indicate that flavocoxid supplement attenuates gentamicin-induced renal injury via the amelioration of oxidative stress and inflammation of renal tubular cells.

Urinary excretion pattern of exosomal aquaporin-2 in rats that received gentamicin.

Urinary exosomes are nano-sized vesicles secreted into urine from all types of renal epithelial cells and are known to contain possible biomarker proteins for renal diseases. Gentamicin has been reported to decrease the level of renal aquaporin (AQP)2, which is known to be mainly expressed in renal collecting ducts and excreted into the urine via exosomes. In the present study, we investigated whether urinary exosomal AQP2 could serve as a potential biomarker for gentamicin-induced nephrotoxicity, especially collecting duct cell dysfunction. Gentamicin was given to rats intraperitoneally once every day starting on day 0. Gentamicin significantly increased the plasma creatinine concentration from day 5 and beyond. Also, gentamicin induced polyuria and a defective urine concentration mechanism on day 7, suggesting gentamicin-induced collecting duct cell dysfunction. Immunoblot analysis showed that gentamicin significantly increased urinary exosomal AQP2 excretion on day 1 but decreased it on day 7 compared with the control group. Similarly, increased excretion of exosomal tumor susceptibility gene 101 protein, frequently used as an exosome marker protein, was observed on day 1. However, gentamicin did not significantly affect the urinary excretion of exosomal tumor susceptibility gene 101 on day 7. Gentamicin slightly decreased renal AQP2 expression on day 2 and markedly decreased it on day 8. These data strongly suggest that the use of urinary exosomal AQP2 as a biomarker may allow detection of gentamicin-induced collecting duct cell dysfunction. Furthermore, urinary exosomal AQP2 might also be useful for the early detection of gentamicin-induced renal injury in addition to collecting duct injury.