Renal Glutathione Research Articles

Effect of verbascoside against acute kidney injury induced by rhabdomyolysis in rats.

Rhabdomyolysis is a pathological condition caused by muscle tissue degradation. In this condition, intracellular contents enter the bloodstream, and acute kidney injury (AKI) develops. Verbascoside (VB) is one of the most common phenylethanoid glycosides and has antioxidant and anti-inflammatory effects. This study investigated the effects of VB on AKI induced by rhabdomyolysis in rats. Male Wistar rats were divided into six groups (n = 6): (1) control group (normal saline), (2) 50% glycerol (10 ml/kg, IM, single injection, only on the first day), (3)-(5) 50% glycerol (same as group 2) + VB (30, 60, and 100 mg/kg, IP, 4 days), and (6) VB (100 mg/kg). Serum and kidney tissue samples were collected on day 5. Subsequently, serum creatinine (Cr), blood urea nitrogen (BUN), renal glutathione (GSH), malondialdehyde (MDA), lipocalin associated with neutrophil gelatinase (NGAL), tumor necrosis factor-alpha (TNF-α), and pathological changes were investigated. The injection of glycerol elevated levels of kidney damage markers, including Cr and BUN in serum, MDA, TNF-α, and NGAL, along with a reduction in GSH levels in the kidney tissue. The administration of VB (100 mg/kg) significantly lowered the levels of these markers, indicating the therapeutic effect of VB against AKI caused by rhabdomyolysis. Histopathological examinations revealed enhanced myoglobin cast formation and tubular necrosis in the glycerol group, which was reduced in rats that received VB, although this reduction did not reach statistical significance. VB can reduce rhabdomyolysis-induced AKI through its anti-inflammatory and antioxidant effects and decrease kidney damage severity.

Monoterpene linalool restrains gentamicin-mediated acute kidney injury in rats by subsiding oxidative stress, apoptosis, and the NF-κB/iNOS/TNF-α/IL-1β pathway and regulating TGF-β.

The clinical use of gentamicin (GM) is restricted by its nephrotoxic effects. This study aimed for the first time to elucidate the ameliorative effects of the monoterpene linalool (Lin) against GM-mediated acute kidney injury in rats. A total of thirty-two rats were subdivided into four equal groups: control (saline), Lin (100mg/kg/day), GM (100mg/kg/day), and GM + Lin (100 and 100mg/kg/day). Lin and GM were intraperitoneally administered for 12 days. Our results illustrated that Lin ameliorated GM-mediated renal histopathological abnormalities and reduced serum urea and creatinine levels in rats exposed to GM. Lin treatment mitigated oxidative stress in nephrotoxic animals as manifested by reducing serum and renal levels of malondialdehyde and increasing the activities of serum and renal glutathione peroxidase and renal catalase. Moreover, Lin markedly inhibited GM-triggered inflammation by downregulating NF-κB, iNOS, TNF-α, and IL-1β and reducing renal myeloperoxidase activity and nitric oxide levels. Interestingly, Lin repressed GM-induced apoptosis, as reflected by a marked downregulation of Bax and caspase-3 expression, concurrent with the upregulation of Bcl2 expression. Finally, Lin administration led to a significant downregulation of TGF-β expression in nephrotoxic animals. In summary, Lin ameliorated GM-mediated nephrotoxicity in rats, at least through its antioxidant, anti-inflammatory, and anti-apoptotic activities and by modulating TGF-β.

Effect of vinpocetine against acrylamide-induced nephrotoxicity in rats.

Vinpocetine (VIN) is a synthetic drug derived from the natural alkaloid vincamine. The antioxidation and anti-inflammation effects of VIN allow it to be used for multiple therapeutic purposes. So, the research aims to discover the possibility of using VIN to improve the nephrotoxicity of acrylamide (ACR). Twenty-four male albino rats were used in the trial: rats in the control group received 0.5 mL of oral saline, rats in the VIN group received an oral dose of VIN (5 mg/kg), rats in the ACR group received an oral dose of ACR (38.27 mg/kg), and rats in the VIN + ACR group received VIN and then ACR 1 h later. Rat blood and kidneys were collected 10 days after the experiment began to assess biochemical parameters and to examine both renal histopathological and immunohistochemistry. The ACR-treated rats showed high levels of serum kidney function biomarkers (creatinine, urea, and uric acid), serum protein biomarkers (total protein, albumin, and globulin), renal kidney injury molecule (KIM)-1, renal malondialdehyde (MDA), and renal caspase-3 immunoexpression. Moreover, ACR lowed both renal superoxide dismutase (SOD) activity and renal glutathione (GSH) level and caused renal histological alterations. While administration of VIN improved serum kidney function biomarkers, serum protein biomarkers, renal KIM-1, renal oxidative stress biomarkers (MDA, SOD, and GSH), renal caspase-3 immunoexpression, and renal histological alterations induced by ACR. The study confirmed the ability of VIN to reduce the nephrotoxic effects of ACR, which was evident through the results of biochemical parameters and histological and immunohistochemical examinations of the kidney tissues.

Cladophora glomerata Kützing extract exhibits antioxidant, anti-inflammation, and anti-nitrosative stress against impairment of renal organic anion transport in an in vivo study.

Cladophora glomerata extract (CGE), rich in polyphenols, was reported to exhibit antidiabetic and renoprotective effects by modulating the functions of protein kinases-mediated organic anion transporter 1 (Oat1) and 3 (Oat3) in rats with type 2 diabetes mellitus (T2DM). Nevertheless, the antioxidant effects of CGE on such renoprotection have not been investigated. This study examined the mechanisms involved in the antioxidant effects of CGE on renal organic anion transport function in an in vivo study. Diabetes was induced in the rats through a high-fat diet combined with a single dose of 40 mg/kg body weight (BW) streptozotocin. Subsequently, normal-diet rats were supplemented with a vehicle or 1,000 mg/kg BW of CGE, while T2DM rats were supplemented with a vehicle, CGE, or 200 mg/kg BW of vitamin C for 12 weeks. The study evaluated the general characteristics of T2DM and renal oxidative stress markers. The renal organic transport function was assessed by measuring the para-aminohippurate (PAH) uptake using renal cortical slices and renal inflammatory cytokine expression in the normal diet (ND) and ND + CGE treated groups. CGE supplementation significantly reduced hyperglycemia, hypertriglyceridemia, insulin resistance, and renal lipid peroxidation in T2DM rats. This was accompanied by the normalization of high expressions of renal glutathione peroxidase and nuclear factor kappa B by CGE and vitamin C. The renal anti-inflammation of CGE was evidenced by the reduction of tumor necrosis factor-1α and interleukin-1β. CGE directly blunted sodium nitroprusside-induced renal oxidative/nitrosative stresses and mediated the PAH uptake in the normally treated CGE in rats was particularly noteworthy. These data also correlated with reduced nitric oxide production, highlighting the potential of CGE as a therapeutic agent for managing T2DM-related renal complications. These findings suggest that CGE has antidiabetic effects and directly prevents diabetic nephropathy through oxidative/nitrosative stress pathways.

Prophylactic Effects of Coriander Aqueous Extract on

A broad spectrum carbamate fungicide called carbendazim (Carb) that is very crucial for preventing plant diseases. and is one of the most pervasive environmental pollutants with serious implications for both human and animal health. In the current study, the role of Coriandrum sativum seeds extract (CSE) on carbendazim induced rats renal toxicity. Carb induced significant elevation in serum creatinine, urea, potassium, kidney malondialdehyde (MDA), nitric oxide (NO), renal injury, PCNA and significant depletion in serum sodium, calcium, renal glutathione (GSH). Treatments of Carb with CSE (CSE+Carb and/or Carb+CSE) improved these parameters and reduced renal toxicity with best results for Carb+CSE than CSE+Carb. Serum phosphorus revealed no significant changes between different groups. The above findings support the hypothesis that the antioxidant characteristics of one or more of CSE constituents can reduce the testicular toxicity of Carb.

Regulation of renal nitric oxide and eNOS/iNOS expression by tadalafil participates in the mitigation of amphotericin B–induced renal injury: Down-regulation of NF-κB/iNOS/caspase-3 signaling

Amphotericin B (AmB)–induced acute kidney injury (AKI) is a common health problem having an undesirable impact on its urgent therapeutic utility for fatal systemic fungal infections. Tadalafil (TAD), a phosphodiesterase-5 (PDE-5) inhibitor, has been observed to have a wide range of pharmacological actions, including nephroprotection. The study’s objective was to examine the possible underlying protective mechanism of TAD against AmB-induced nephrotoxicity. Experimentally, animals were divided randomly into four groups: control, TAD (5 mg/kg/day; p.o.), AmB (18.5 mg/kg/day; i.p.), and TAD+AmB groups. Sera and tissue samples were processed for biochemical, molecular, and histological analyses. The biochemical investigations showed that TAD significantly ameliorated the increase of kidney function biomarkers (creatinine, urea, CysC, KIM-1) in serum, renal nitric oxide (NO), lipid peroxidation (MDA), and inflammatory cytokines (TNF-α, IL-6) in AmB-treated rats. Meanwhile, TAD significantly retarded AmB-induced decrease in serum magnesium, sodium, potassium, and renal glutathione content. Molecular analysis revealed that TAD reduced AmB-induced imbalance in the protein expression of eNOS/iNOS, which explains its regulatory effect on renal NO content. These results were also supported by the down-regulation of nuclear NF-κB p65 and cleaved caspase-3 protein expressions, as well as the improvement of histological features by TAD in AmB-treated rats. Therefore, it can be suggested that TAD could be a promising candidate for renoprotection against AmB-induced AKI. That could be partly attributed to its regulatory effect on renal eNOS/iNOS balance and NO, the inhibition of NF-κB p65 nuclear translocation, its downstream inflammatory cytokines and iNOS, and ultimately the inhibition of caspase-3-induced renal apoptosis.

Selenium deficiency causes hypertension by increasing renal AT1 receptor expression via GPx1/H2O2/NF-κB pathway.

Epidemiological studies show an association between low body selenium and the risk of hypertension. However, whether selenium deficiency causes hypertension remains unknown. Here, we report that Sprague-Dawley rats fed a selenium-deficient diet for 16 weeks developed hypertension, accompanied with decreased sodium excretion. The hypertension of selenium-deficient rats was associated with increased renal angiotensin II type 1 receptor (AT1R) expression and function that was reflected by the increase in sodium excretion after the intrarenal infusion of the AT1R antagonist candesartan. Selenium-deficient rats had increased systemic and renal oxidative stress; treatment with the antioxidant tempol for 4 weeks decreased the elevated blood pressure, increased sodium excretion, and normalized renal AT1R expression. Among the altered selenoproteins in selenium-deficient rats, the decrease in renal glutathione peroxidase 1 (GPx1) expression was most prominent. GPx1, via regulation of NF-κB p65 expression and activity, was involved in the regulation of renal AT1R expression because treatment with dithiocarbamate (PDTC), an NF-κB inhibitor, reversed the up-regulation of AT1R expression in selenium-deficient renal proximal tubule (RPT) cells. The up-regulation of AT1R expression with GPx1 silencing was restored by PDTC. Moreover, treatment with ebselen, a GPX1 mimic, reduced the increased renal AT1R expression, Na+-K+-ATPase activity, hydrogen peroxide (H2O2) generation, and the nuclear translocation of NF-κB p65 protein in selenium-deficient RPT cells. Our results demonstrated that long-term selenium deficiency causes hypertension, which is due, at least in part, to decreased urine sodium excretion. Selenium deficiency increases H2O2 production by reducing GPx1 expression, which enhances NF-κB activity, increases renal AT1R expression, causes sodium retention and consequently increases blood pressure.

Impact of peroxisome proliferator activated receptor agonist drugs in a model of nephrotoxicity in rats.

Doxorubicin (DOX) is one of the basic anticancer drugs, nonetheless its use is restricted due to noxious side effects. Kidney failure is one of the main side effects that restrict its medical use. The current study assessed the nephroprotective effects of fenofibrate and pioglitazone against the renal injury induced by doxorubicin in rats and illustrated the probable mechanisms underlying these protective effects. For this purpose, Male Sprague-Dawley rats weighing (200-230 g) were allocated into seven groups treated for 15 days as following: control (50% corn oil + 50% DMSO p.o), fenofibrate (100 mg/kg p.o) and pioglitazone (10 mg/kg p.o) as well as four groups of DOX (15 mg/kg i.p on 11th day). DOX groups included DOX alone and DOX with protective drugs fenofibrate, pioglitazone or both of them. As a result of doxorubicin nephrotoxicity; serum creatinine and blood urea nitrogen were remarkably elevated. Moreover, renal glutathione was significantly reduced while tissue lipid peroxidation malondialdehyde, tumor necrosis factor-α, nuclear factor-kappa B p65 (NF-κB p65), interleukin-1β, p38 mitogen activated protein kinase (p38-MAPK) and caspase-3 (Casp-3) were significantly augmented. Treatment with fenofibrate and pioglitazone either alone or in combination markedly attenuated DOX-induced injury by suppression of oxidative stress, inflammation and apoptosis. The above-mentioned biochemical markers were affirmed by histological assessment. In conclusion, fenofibrate, pioglitazone, and their combination possess potential prophylactic effects against doxorubicin-induced renal injury through modulation of p38-MAPK/NF-κB p65 pathway with superiority to the combination.

Renal Tubular Cell Ferroptosis: A New Player in Pathogenesis of Lupus Nephritis

Abstract Background New research indicates that the injury to the renal tubular epithelial cells is a better predictor of renal outcomes in lupus nephritis (LN) as compared to glomerular injury. Iron accumulates mostly in the renal tubular cells of LN patients and murine models of LN. Ferroptosis is an incompletely understood form of cell death involving iron mediated lipid peroxidation, but its role in LN is not well established. Experiment LN and control patient biopsies were stained for markers of ferroptosis. Kidneys of female (MRL/lpr) and male (NZW X BXSB) F1, lupus mice were analyzed for markers of ferroptosis. Human proximal tubular cells (PTEC) were treated with LN serum with or without Liporxstatin-2, a novel ferroptosis inhibitor. Results Compared to controls, LN patients expressed higher levels of ACSL4 and 4HNE, the ferroptosis core proteins in the renal tubules. Compared to non-nephritic mice, nephritic mice had significantly higher gene expression of Aifm2, Acsl4, and Gpx1 as well as protein levels of Acsl4. Nephritic mice had an impaired renal glutathione synthesis pathway. Glutathione is an essential positive regulator of glutathione peroxidase 4 (Gpx4: ferroptosis inhibitor) which resulted in lower protein expression of Gpx4. Collectively, LN kidneys displayed a ferroptosis signature and was associated with an increase in Ngal and Kim1, PTEC injury markers. LN patients’ serum induced PTEC ferroptosis and associated pathology were significantly reduced by Liproxstatin-2. Conclusion Our data identify occurrence ferroptosis in renal tubular cell which can contribute to the pathogenesis of LN. Liproxstatin-2 mitigates human LN serum induced PTEC pathology and holds promise as an adjunct therapy to alleviate LN severity. Supported by grants from Vifor Pharma

Supplementation of conventional anti-diabetic therapy with alpha-lipoic acid prevents early development and progression of diabetic nephropathy

BackgroundDiabetic nephropathy (DN) is the leading cause of end-stage renal disease. Current pharmacological interventions only retard DN progression. Alpha-lipoic acid (ALA) is a potent antioxidant with beneficial effect in other diabetic complications. This study investigates whether ALA supplementation prevents early development and progression of DN. MethodFifty-eight male Sprague-Dawley rats were randomly assigned to healthy control and diabetic groups and subjected to overnight fasting. Type 2 diabetes mellitus (T2DM) was induced in diabetic group by intraperitoneal administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). On day 3 after T2DM induction, diabetic rats received oral daily administration of ALA (60 mg/kg), gliclazide (15 mg/kg), ramipril (10 mg/kg) or drug combinations for 6 weeks. Untreated diabetic rats served as diabetic control. Blood, kidneys and pancreas were harvested for biochemical and histological analyses. ResultInduction of T2DM resulted in hypoinsulinemia, hyperglycemia and renal pathology. ALA supplementation maintained β-cell function, normoinsulinemia and normoglycemia in diabetic rats, and prevented renal pathology (PAS, KIM-1, plasma creatinine, total protein, blood urea nitrogen, uric acid and urine albumin/creatinine ratio) and triglycerides level compared to diabetic control (p < 0.001). Additionally, ALA supplementation significantly prevented elevated serum and tissue malondialdehyde, collagen deposition, α-SMA expression, apoptosis and serum IL-1β and IL-6 levels while it markedly increased renal glutathione content and plasma HDL-C compared to diabetic control group (p < 0.001). ConclusionALA supplementation prevents early development and progression of DN by exerting anti-hyperglycemic, antioxidant, anti-inflammatory, anti-fibrotic and anti-apoptotic effects. Our findings provide additional option for clinical treatment of DN in T2DM patients.

Glutathione is an aging-related metabolic signature in the mouse kidney.

The ability to maintain systemic metabolic homeostasis through various mechanisms represents a crucial strength of kidneys in the study of metabolic syndrome or aging. Moreover, age-associated kidney failure has been widely accepted. However, efforts to demonstrate aging-dependent renal metabolic rewiring have been limited.In the present study, we investigated aging-related renal metabolic determinants by integrating metabolomic and transcriptomic data sets from kidneys of young (3 months, n = 7 and 3 for respectively) and old (24 months, n = 8 and 3 for respectively) naive C57BL/6 male mice. Metabolite profiling analysis was conducted, followed by data processing via network and pathway analyses, to identify differential metabolites. In the aged group, the levels of glutathione and oxidized glutathione were significantly increased, but the levels of gamma-glutamyl amino acids, amino acids combined with the gamma-glutamyl moiety from glutathione by membrane transpeptidases, and circulating glutathione levels were decreased. In transcriptomic analysis, differential expression of metabolic enzymes is consistent with the hypothesis of aging-dependent rewiring in renal glutathione metabolism; pathway and network analyses further revealed the increased expression of immune-related genes in the aged group.Collectively, our integrative analysis results revealed that defective renal glutathione metabolism is a signature of renal aging. Therefore, we hypothesize that restraining renal glutathione metabolism might alleviate or delay age-associated renal metabolic deterioration, and aberrant activation of the renal immune system.

Biological activity and subchronic toxicity study of Allanblackia floribunda Oliv. on experimental rats

Allanblackia floribunda Oliv. (Elephant rice) belongs to the family Clusiaceae. It is confined to tropical Africa where it is used traditionally for the treatment of malaria, asthma and inflammatory diseases. This study evaluated the biological activity of methanol extract of A. floribunda's stem bark and leaf in addition to the seed oil as well as the subchronic toxicity of the stem bark extract. Standards procedures were used to screen the biological activity of A. floribunda. The subchronic toxicity profile was investigated by administering orally 100, 300 and 600 mg/kg b. wt of the stem bark extract to male Albino rats for 28 days consecutively. After the treatment period, changes in the various biochemical parameters and alteration in the expression of antioxidants, cytokine, Kidney injury molecule-1 (KIM-1) and albumin genes of the sensitive organs were used to assess the safety level of the stem bark extract. The stem bark extract had more phytochemicals and better antioxidant activities compared with the leaf extract and oil. Administration of the stem bark extract did not result in treatment related changes in markers for hepatic and renal injury (aspartate transaminase, alanine transaminase, total protein, albumin, globulin, creatinine and urea). The extract resulted in an increase in hepatic malondialdehyde. Also, hepatic and renal glutathione levels increased significantly. The blood composition was normal and the genes coding for albumin in the liver together with catalase in the liver and kidney were up-regulated. Tumor necrosis factor – alpha (TNFα) gene expression was down-regulated in the liver and up-regulated in the kidney while KIM-1 gene was down-regulated in the treated animals compared with the control. This study confirmed that A. floribunda's stem bark extract is richer in bioactive compounds than the leaf extract and seed oil. Furthermore, it is relatively safe to animals when used in moderate dose.

Protective Effects of Low Dose Vorinostat on Cisplatin-Induced Nephrotoxicity in Rats.

Cisplatin (cis-diamminedichloroplatinum [II]; CDDP) is the most widely used drug in cancer chemotherapy. The nephrotoxicity of CDDP is one of its major side effects. Vorinostat (VST) has been reported to have antioxidant and anti-inflammatory effects in bothin-vitro and in vivo models. The present study aimed to explore the potential protective effects of VST against CDDP-induced nephrotoxicity in rats. The rats were randomly divided into 4 groups; control group, CDDP group (received CDDP 7.5 mg/kg IP single dose 5 days before the end of the experiment), VST group, (received VST 15 mg/kg/day by gastric gavage for 28 days), and CDDP + VST group (received CDDP + VST as above). Blood and kidney samples were collected on the 28th day for biochemical and histopathological examinations. Administration of CDDP single dose (7.5 mg/kg IP) 5 days before the end of the experiment (at day 23) produced a significant decrease in renal glutathione levels and a significant increase in serum urea nitrogen, creatinine, renal malondialdehyde, tumor necrosis factor-alpha, tumor suppressor protein (p53) and nuclear factor kappa B levels compared to the control group. Pretreatment with VST for 28 days significantly attenuated all unfavorable changes of these parameters. Histopathological analysis showed that VST significantly decreased kidney inflammatory and degenerative changes induced by CDDP. VST also significantly increased Bcl-2 and decreased Caspas- 3 immunoexpression in renal tissues. These results suggest that VST alleviates CDDP-induced nephrotoxicity in rats showing a novel therapeutic potential for the management of nephrotoxicity induced by CDDP.

Genetic mapping of renal glutathione suggests a novel regulatory locus on the murine X chromosome and overlap with hepatic glutathione regulation

Glutathione (GSH) is a critical cellular antioxidant that protects against byproducts of aerobic metabolism and other reactive electrophiles to prevent oxidative stress and cell death. Proper maintenance of its reduced form, GSH, in excess of its oxidized form, GSSG, prevents oxidative stress in the kidney and protects against the development of chronic kidney disease. Evidence has indicated that renal concentrations of GSH and GSSG, as well as their ratio GSH/GSSG, are moderately heritable, and past research has identified polymorphisms and candidate genes associated with these phenotypes in mice. Yet those discoveries were made with in silico mapping methods that are prone to false positives and power limitations, so the true loci and candidate genes that control renal glutathione remain unknown. The present study utilized high-resolution gene mapping with the Diversity Outbred mouse stock to identify causal loci underlying variation in renal GSH levels and redox status. Mapping output identified a suggestive locus associated with renal GSH on murine chromosome X at 51.602 Mbp, and bioinformatic analyses identified apoptosis-inducing factor mitochondria-associated 1 (Aifm1) as the most plausible candidate. Then, mapping outputs were compiled and compared against the genetic architecture of the hepatic GSH system, and we discovered a locus on murine chromosome 14 that overlaps between hepatic GSH concentrations and renal GSH redox potential. Overall, the results support our previously proposed model that the GSH redox system is regulated by both global and tissue-specific loci, vastly improving our understanding of GSH and its regulation and proposing new candidate genes for future mechanistic studies.

Protective effect of alamandine on doxorubicin\u2011induced nephrotoxicity in rats

BackgroundThis study aimed to evaluate the protective effects of alamandine, a new member of the angiotensin family, against doxorubicin (DOX)-induced nephrotoxicity in rats.MethodsRats were intraperitoneally injected with DOX (3.750 mg/kg/week) to reach a total cumulative dose of 15 mg/kg by day 35. Alamandine (50 µg/kg/day) was administered to the rats via mini-osmotic pumps for 42 days. At the end of the experiment, rats were placed in the metabolic cages for 24 h so that their water intake and urine output could be measured. After scarification, the rats’ serum and kidney tissues were collected, and biochemical, histopathological, and immunohistochemical studies were carried out.ResultsDOX administration yielded increases in pro-inflammatory cytokines, including interleukin (IL)-1β and IL-6, pro-fibrotic proteins transforming growth factor-β (TGF-β), pro-inflammatory transcription factor nuclear kappa B (NF-κB), kidney malondialdehyde (MDA), creatinine clearance, blood urea nitrogen (BUN), and water intake. On the other hand, the DOX-treated group exhibited decreased renal superoxide dismutase (SOD), renal glutathione peroxidase (GPx) activity, and urinary output. Alamandine co-therapy decreased these effects, as confirmed by histopathology and immunohistochemical analysis.ConclusionsThe results suggest that alamandine can prevent nephrotoxicity induced by DOX‎ in rats.

The therapeutic potential of curcumin in alleviating N-diethylnitrosamine and iron nitrilotriacetate induced renal cell tumours in mice via inhibition of oxidative stress: Implications for cancer chemoprevention

This study was designed to reveal the protective effects of dietary supplementation of curcumin against renal cell tumours and oxidative stress induced by renal carcinogen iron nitrilotriacetate (Fe-NTA) in ddY male mice. The results showed that mice treated with a renal carcinogen, Fe-NTA, a 35% renal cell tumour incidence was noticed, whereas renal cell tumour occurrence was elevated to 80% in Fe-NTA promoted and N-diethylnitrosamine (DEN)-initiated mice as compared with saline- treated mice. No incidence of tumours has been observed in DEN-initiated non-promoted mice. Diet complemented with 0.5% and 1.0% curcumin fed prior to, during and after treatment with Fe-NTA in DEN-initiated animals, tumour incidence was reduced dose-dependently to about 45% and 30% respectively. Immunohistochemical studies also revealed the increased formation of 4-hydroxy-2-nonenal (HNE)-modified protein adducts and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in kidney tissue of mice treated with an intraperitoneal injection of Fe-NTA (6.0 mg Fe/kg body weight.). Furthermore, Fe-NTA treatment of mice also resulted in significant elevation of malondialdehyde (MDA), serum urea, and creatinine and decreases renal glutathione. However, the changes in most of these parameters were attenuated dose-dependently by prophylactic treatment of animals with 0.5% and 1% curcumin diet, this may be due to its antioxidative impact of curcumin. These results suggest that intake of curcumin is beneficial for the prevention of renal cell tumours and oxidative stress damage mediated by renal carcinogen, Fe-NTA.

Effectiveness of N-Acetylcysteine in the Treatment of Renal Deterioration Caused by Long-Term Exposure to Bisphenol A.

Human health hazards caused by bisphenol A (BPA), a precursor for epoxy resins and polycarbonate-based plastics, are well documented and are closely associated with mitochondrial impairment and oxidative imbalance. This study aimed to assess the therapeutic efficacy of N-acetylcysteine (NAC) on renal deterioration caused by long-term BPA exposure and examine the signaling transduction pathway involved. Male Wistar rats were given vehicle or BPA orally for 12 weeks then the BPA-treated group was subdivided to receive vehicle or NAC concurrently with BPA for a further 4 weeks, while the vehicle-treated normal control group continued to receive vehicle through to the end of experiment. Proteinuria, azotemia, glomerular filtration reduction and histopathological abnormalities caused by chronic BPA exposure were significantly reduced following NAC therapy. NAC also diminished nitric oxide and lipid peroxidation but enhanced renal glutathione levels, and counteracted BPA-induced mitochondrial swelling, increased mitochondrial reactive oxygen species production, and the loss of mitochondrial membrane potential. The benefit of NAC was related to the modulation of signaling proteins in the AMPK-SIRT3-SOD2 axis. The present study shows the potential of NAC to restore mitochondrial integrity and oxidative balance after long-term BPA exposure, and suggests that NAC therapy is an effective approach to tackle renal deterioration in this condition.

Evening Primrose Oil/ Vitamin E Combination Treatment Has Renoprotective Effect On Gentamicin-Induced Nephrotoxicity By Suppressing Renal Tumor Necrosis Factor α (TNF-α) / Nuclear Factor κβ (NF- κβ) Pathway And Inhibiting Renal Oxidative Stress

Gentamicin is an effective aminoglycoside antibiotic drug but unfortunately up to 30% of gentamicin-treated patients may develop nephrotoxicity. Suggested mechanisms of gentamicin-induced nephrotoxicity included inflammation and oxidative stress injury. Evening primrose oil (EPO) has anti-inflammatory and antioxidant effects. The aim of current study was to assess the possible renoprotective effect of EPO/vitamin E combination treatment on gentamicin-induced nephrotoxicity in rats. Additionally, to address the responsible mechanism(s) of this effect. Eighteen adult male albino Sprague-Dawley rats were equally and randomly divided into three groups; normal control, gentamicin control and EPO/vitamin E treated groups. Gentamicin control group and EPO/vitamin E treated group received IP gentamicin injections for 5 days (100 mg/kg). EPO/vitamin E treated group received EPO/vitamin E (10 g and 200 IU /kg/day respectively orally). Renal function, oxidative stress and histopathological changes were assessed. Renal tissue expressions of tumor necrosis factor α (TNF α) and nuclear Factor κβ (NF- κβ) were assayed. Significant improvements of kidney function markers and tubular necrosis in EPO/vitamin E treated group were observed. EPO/vitamin E treatment significantly ameliorated the gentamicin-induced increase of renal lipid peroxidation and renal tissue expression of TNF α and NF-κβ. EPO/vitamin E treatment significantly ameliorated the gentamicin-induced decrease of renal glutathione and superoxide dismutase concentrations. Conclusion of current study is EPO/vitamin E combination treatment has renoprotective effect on gentamicin-induced nephrotoxicity by inhibiting renal TNF α /NF-κβ signaling pathway and the oxidative stress. Further researches for addressing the renoprotective effect of EPO treatment only and to determine other possible responsible mechanisms are needed.

EXPERIMENTAL THERAPEUTIC EVALUATION OF THE AFRICAN VEGETABLES (CLERODENDRUM VOLUBILE LEAF AND IRVINGIA GABONENSIS SEED EXTRACTS) IN TRASTUZUMAB-MEDIATED HEPATO-RENAL DYSFUNCTION IN WISTAR RATS

Objective: The use of trastuzumab (TZM) in the clinical management of human epidermal growth factor receptor 2 positive metastatic breast and gastric cancers, gastro-esophageal adenocarcinoma, and colorectal carcinoma has been limited by its off-target cardiac, hepatic, and renal toxicities which till date have no effective therapies in either their prevention or amelioration. Thus, the present study is designed at investigating the protective and therapeutic potentials of 400 mg/kg/day Clerodendrum volubile ethanol leaf extract (CVE) and Irvingia gabonensis ethanol seed extract (IGE) pretreatments in TZM-intoxicated Wistar rats based on their reported folkloric use in the local management of kidney and liver diseases and the previously reported therapeutic potential of these African vegetables in TZM cardiotoxicity.&#x0D; Methods: Forty-nine male Wistar rats were randomly allotted into seven groups of seven rats per group. Group I rats were treated with 10 ml/kg/day of 5% dimethyl sulfoxide (DMSO) sterile water p.o. and 1 ml/kg/day 5% DMSO sterile water i.p.; Groups II and III rats were orally pretreated with 400 mg/kg/day CVE and IGE, respectively, 3 h before 1 ml/kg/day/i.p. 5% DMSO sterile water; Group IV rats were orally pretreated with 10 ml/kg/day 5% DMSO sterile water 3 h before 2.25 mg/kg/day/i.p. TZM; and Groups V-VII rats were pretreated with 20 mg/kg/day Vit. C, 400 mg/kg/day CVE, and 400 mg/kg/day IGE all dissolved in 5% DMSO sterile water, respectively, 3 h before i.p. injections of 2.25 mg/kg/day TZM, all for 7 days. Liver function parameters, renal function parameters, oxidative stress markers, and histopathological investigations were the study measuring endpoints.&#x0D; Results: Oral pretreatment with 20 mg/kg/day Vit. C, 400 mg/kg/day CVE and IGE significantly ameliorated TZM-mediated hepatic and renal toxicities by effectively lowering the serum alanine transaminase, aspartate transaminase, alkaline phosphatase, creatinine, and urea levels. CVE and IGE pretreatments also significantly reversed TZM-induced decreases in the hepatic and renal tissue catalase, superoxide dismutase, and glutathione- S-transferase activities and reduced malondialdehyde levels. CVE and IGE pretreatments also improved TZM-induced hepatic and renal histological lesions.&#x0D; Conclusions: Overall, the chemotherapeutic/chemopreventive potentials of CVE and IGE in TZM-induced hepatorenal dysfunction were either wholly or partly mediated through free-radical scavenging and antioxidant activities.

Suppression of Adenosine Deaminase and Xanthine Oxidase Activities by Mineralocorticoid and Glucocorticoid Receptor Blockades Restores Renal Antioxidative Barrier in Oral Contraceptive-Treated Dam.

Objective We tested the hypothesis that postpartum combined oral contraceptive (COC) treatment would induce oxidative stress via the adenosine deaminase-xanthine oxidase pathway in the kidney. We also sought to determine whether mineralocorticoid receptor (MR) or glucocorticoid receptor (GR ) blockade would suppress the activities of ADA and xanthine oxidase caused by postpartum COC treatment in the kidney. Methods Twenty-four Wistar dams were randomly assigned to 4 groups (n = 6/group). Dams received vehicle (po), COC (1.0 μg ethinylestradiol and 5.0 μg levonorgestrel; po), COC with GR blockade (mifepristone; 80.0 mg/kg; po), and COC with MR blockade (spironolactone; 0.25 mg/kg; po) daily between 3rd and 11th week postpartum. Results Data showed that postpartum COC caused increased plasma creatinine and urea, increased renal triglyceride/high-density lipoprotein ratio, free fatty acid accumulation, alanine aminotransferase, gamma-glutamyltransferase, uric acid, and activities of renal XO and ADA. On the other hand, postpartum COC resulted in decreased plasma albumin, renal glutathione, and Na+-K+-ATPase activity with no effect on lactate production. However, MR or GR blockade ameliorated the alterations induced by postpartum COC treatment. The present results demonstrate that MR or GR blockade ameliorates postpartum COC-induced increased activities of ADA and xanthine oxidase and restores glutathione-dependent antioxidative defense. Conclusion These findings implicate the involvements of GR and MR in renal dysfunctions caused by COC in dams via disrupted glutathione antioxidative barrier.