Renal Thiobarbituric Acid Reactive Substances Research Articles

The Haematotoxicity and Nephrotoxicity Effects of Diazepam Administration in Male Albino Rats

Objectives: This study aimed to assess the haematological and nephrotoxic effects of diazepam at varying doses in male albino rats. Materials and Methods: Rats were administered therapeutic (0.062 mg/kg/day), high (0.33 mg/kg/day), and extremely high (0.661 mg/kg/day) doses of diazepam orally for 14 and 28 days. Blood and kidney samples were collected for haematological and biochemical analysis.Results: Diazepam administration significantly reduced red blood cell count (RBC), packed cell volume (PCV), and platelet count (PLT), while other haematological indices were not notably affected. Plasma creatinine and urea levels increased, and total protein decreased across all doses. The treatment also elevated renal thiobarbituric acid reactive substances (TBARS) levels, while reducing antioxidant enzyme activity superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH). Conclusions: Diazepam poses significant risks of oxidative stress, haematotoxicity, and nephrotoxicity. While effective in managing anxiety, caution is necessary due to its potentially harmful effects on blood and renal function.

Nephroprotective effect of diosmin against sodium arsenite-induced renal toxicity is mediated via attenuation of oxidative stress and inflammation in mice

Arsenic compounds, which are used in different industries like pesticide manufacturing, cause severe toxic effects in almost all organs, including the kidneys. Since the primary route of exposure to arsenic is through drinking water, and millions of people worldwide are exposed to unsafe levels of arsenic that can pose a threat to their health, this research was performed to investigate the nephroprotective effects of Diosmin (Dios), a flavonoid found in citrus fruits, against nephrotoxicity induced by sodium arsenite (SA). To induce nephrotoxicity, SA (10 mg/kg, oral gavage) was administered to mice for 30 days. Dios (25, 50, and 100 mg/kg, oral gavage) was given to mice for 30 days prior to SA administration. After the study was completed, animals were euthanized and blood and kidney samples were taken for biochemical and histopathological assessments. Results showed that SA-treated mice significantly increased the blood urea nitrogen and creatinine levels in the serum. This increase was associated with significant kidney tissue damage in SA-treated mice, which was confirmed by histopathological studies. Furthermore, SA enhanced the amounts of renal thiobarbituric acid reactive substances and decreased total thiol reserves, as well as the activity of antioxidant enzymes such as catalase, superoxide dismutase, and glutathione peroxidase. Also, in the SA-exposed group, an increase in the levels of kidney inflammatory biomarkers, including nitric oxide and tumor necrosis factor-alpha was observed. The western blot analysis indicated an elevation in the protein expression of kidney injury molecule-1 and nuclear factor-kappa B in SA-treated mice. However, pretreatment with Dios ameliorated the SA-related renal damage in mice. Our findings suggest that Dios can protect the kidneys against the nephrotoxic effects of SA by its antioxidant and anti-inflammatory characteristics.

Febuxostat ameliorates high salt intake-induced hypertension and renal damage in Dahl salt-sensitive rats.

Several clinical studies have reported that xanthine oxidoreductase inhibitors have antihypertensive and renal protective effects but their mechanisms have not been fully determined. This study aims to clarify these mechanisms by examining the effects of febuxostat, which is a novel selective xanthine oxidoreductase inhibitor, in Dahl salt-sensitive rats. Eight-week-old male Dahl salt-sensitive rats were fed a normal salt (0.6% NaCl) or high salt (8% NaCl) diet for 8 weeks. A portion of the rats that were fed high salt diet were treated with febuxostat (3 mg/kg per day) simultaneously. Additionally, acute effects of febuxostat (3 mg/kg per day) were examined after high salt diet feeding for 4 or 8 weeks. Treatment with febuxostat for 8 weeks attenuated high salt diet-induced hypertension, renal dysfunction, glomerular injury, and renal interstitial fibrosis. Febuxostat treatment reduced urinary excretion of H2O2 and malondialdehyde and renal thiobarbituric acid reactive substances content. High salt diet increased xanthine oxidoreductase activity and expression in the proximal tubules and medullary interstitium. Febuxostat completely inhibited xanthine oxidoreductase activity and attenuated the high salt diet-increased xanthine oxidoreductase expression. Febuxostat transiently increased urine volume and Na+ excretion without change in blood pressure or urinary creatinine excretion after high salt diet feeding for 4 or 8 weeks. Febuxostat ameliorates high salt diet-induced hypertension and renal damage with a reduction of renal oxidative stress in Dahl salt-sensitive rats. The antihypertensive effect of febuxostat may be mediated in part by diuretic and natriuretic action.

Ameliorative Effects of Annona muricata (Graviola) and Fullerene C60 Against Toxicity Induced by Carboplatin in Male Albino Rats

This study was designed to demonstrate the ameliorating effects Annona muricata (Graviola)plant extract and fullerene C60 on hematological and biochemical disorder alteration induced by intraperitoneal (i.p.) injection of carboplatin (CRP) on male rats. Five groups of adult male rats we established (n=10). Group1: animals were administered normal saline i.p. (10 ml/kg b.wt) for 40 days and served as a normal group. Group 2: rats were injected i.p. with a single dose of CRP (80 mg/kg b.wt), then received a saline solution for the remaining 40 days and served as a control group. Group 3: animals were oral administration of Annona muricata leaves extract at a dose of 200 mg/kg/day for 40 consecutive days after 24 hours of i.p. injected with a single dose of CRP (80 mg/kg b.wt.). Group 4: animals weretreated orally by fullerene C60 (4 mg/ kg b.wt.) daily for 40 daysafter 24 hours of i.p. injected a single dose of CRP (80 mg/kg b.wt.). Group 5: each rat in this group was daily oral administration of Annona muricata leaves extract at a dose of (200 mg/kg b.wt.)+ fullerene C60 (4 mg/ kg b. wt.) for 40 days after 24 hours of injected a single dose of CRP. Results obtained revealed that CRP administration in the control group (gp. 2) significantly reduced the levels of red blood cells (RBCs), haemoglobin (Hb), blood Platelets (PLTs) and PCV value, with a marked reduction in white blood cells (WBCs). Additionally, there is an elevation in serum ALT, AST, ALP, total bilirubin, creatinine and urea associated with a reduction in albumin, total protein, and uric acid. In addition, hepatic and renal thiobarbituric acid reactive substances (TBARS) levels were significantly increased by CRP administration while levels of endogenous antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) were reduced. This study confirmed the risk of increased oxidative stress, hepatotoxicity and nephrotoxicity due to CRP administration. In addition, Annona muricata leaves extractand fullerene C60, clarifiedmodulatory role against the cellular damage produced by free radical-induced by CRP.

EFFECT OF CUCUMIS MELO VAR. FLEXUOSUS LEAVES EXTRACT ON RENAL OXIDATIVE INJURY AND INFLAMMATION IN DIABETIC MALE ALBINO RATS

Kidney disorders are common complications of uncontrolled diabetes. The present study aimed to evaluate the effect of oral administration of Cucumis melo var. flexuosus (snake melon or faqqous) leaves extract in three different doses (30, 60 and 120 mg/kg body weight) for 30 consecutive days on renal damage and inflammation in streptozotocin (STZ)-induced diabetic male albino rats (single intraperitoneal injection of 60 mg STZ/kg body weight). The results showed that the snake melon leaves extract induced a significant decrease in the plasma level of the kidney injury molecule-1 (KIM-1) in the diabetic rats. In addition, the snake melon leaves extract caused a significant decrease in the levels of the renal thiobarbituric acid reactive substances (TBARS), tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and caspase-3 of the diabetic rats. On the other hand, renal catalase (CAT) and superoxide dismutase (SOD) activities, as well as renal vascular endothelial growth factor (VEGF) level, were elevated significantly in the diabetic rats treated only with 60 mg or 120 mg of the snake melon leaves extract/kg body weight (compared with the diabetic control rats). In conclusion, the results of the present study revealed that the snake melon leaves extracts have a potential and effective role in inhibiting inflammation and oxidative stress in the kidney of diabetic rats.

Codeine-mediated Haematoxicity, Hepatotoxicity and Nephrotoxicity in Male Albino Rats

Objectives: This study aimed to investigate the effects of codeine administration on some haematological and biochemical indices in rats.
 Materials and Methods: Therapeutic dose (5 mg/kg/day), high dose (25 mg/kg/day) and extreme dose (50 mg/kg/day) of codeine were administered orally to rats for 28 days. Twenty-four hours after the last codeine administration, blood, liver and kidney were removed from the animals after an overnight fast and analysed for their haematological and biochemical parameters.
 Results: Results obtained revealed that codeine administration significantly reduced the levels of white blood cells (WBC), red blood cell (RBC) and platelet count (PLT) and increased the levels of mean corpuscular haemoglobin (MCH) and mean corpuscular volume (MCV)while it resulted in non-significant changes in other haematological parameters examined when compared with control rats. Codeine intake significantly increased plasma levels of alkaline phosphatase (ALP), aspartate aminotransferase (AST), creatinine and urea while its reduced total protein levels. Hepatic and renal thiobarbituric acid reactive substances (TBARS) levels were significantly increased by codeine administration while levels of endogenous antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) were reduced.
 Conclusions: This study confirmed the risk of increased oxidative stress, haematoxicity, hepatotoxicity and nephrotoxicity due to codeine administration. Although codeine is reported to be effective in pain management, its toxicity should be kept in mind.

Hematological and Biochemical Changes in Blood, Liver and Kidney Tissues under the Effect of Tramadol Treatment

This study aimed to investigate the effects of tramadol administration on some haematological and biochemical indices in rats. Tramadol was administered orally to rats for 28 days at a dose of 10 mg/kg body weight/day, 50 mg/kg body weight/day and 100 mg/kg body weight/day. Twenty-four hours after the last tramadol, blood, liver and kidney were removed from the animals after an overnight fast and analysed for their haematological and biochemical parameters. Results obtained revealed that tramadol administration significantly reduced the levels of white blood cells (WBC), red blood cell (RBC), haemoglobin and platelet count (PLT) while its resulted in non-significant changes in other haematological parameters examined when compared with control rats. Tramadol intake significantly increased plasma levels of alkaline phosphatase (ALP), aspartate aminotransferase (AST), creatinine and urea while its reduced total protein levels. Hepatic and renal thiobarbituric acid reactive substances (TBARS) levels were significantly increased by tramadol administration while levels of endogenous antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) were reduced. This study confirmed the risk of increased oxidative stress, hepatotoxicity and nephrotoxicity due to tramadol administration. Although tramadol is reported to be effective in pain management, its toxicity should be kept in mind.

Effect of quercetin on the anti-tumor activity of cisplatin in EMT6 breast tumor-bearing mice.

ObjectiveThe purpose of this study was to determine the effect of quercetin on the antitumor activity of cisplatin and its side-effects.MethodsEMT6 cells, a mouse breast cancer cell line, were injected subcutaneously in mice to generate a breast tumor-bearing mouse model. Experimental groups were divided into four groups: control (C), quercetin (Q), cisplatin (CP), and cisplatin+quercetin (CP+Q).ResultsThe tumor volume of the CP+Q group was significantly lower than that of the CP group. Serum blood urea nitrogen and creatinine levels in the CP+Q group were lower than those in the CP group. Renal γ-glutamyltranspeptidase and alkaline phosphatase activities were significantly higher in the CP+Q group than in the CP group, and the content of renal thiobarbituric acid reactive substance was significantly lower in the CP+Q group than that in the CP group. These results suggested that quercetin and cisplatin synergistically increased cellular toxicity in breast cancer cells and mediated cancer growth inhibition, thereby enhancing the antitumor effect of cisplatin compared to when only cisplatin was administered. Quercetin also reduced renal toxicity, which arose as a potential a side effect of cisplatin.ConclusionThe enhanced antitumor effect of cisplatin and decreased renal toxicity after quercetin treatment suggested the applicability of quercetin as an adjuvant for chemotherapeutic agents.

Nephrotoxicity in Hybrid sparrow (Passer domesticus × Passer hispaniolensis) living near a phosphate treatment factory complex in southern Tunisia: a biochemical and histological study.

Our study was designed to evaluate impacts of exposure to pollutants, released by the Gabès-Ghannouche factory complex of phosphate treatment, on biochemical biomarkers and histopathological indices in kidney tissues of Hybrid sparrow (Passer domesticus × Passer hispaniolensis) in Gabès city. Our results show evidence of a pronounced impairment in kidney function which is confirmed by remarkable blood chemical alterations in sparrows living in Ghannouche, the most polluted site. Moreover, superoxide dismutase and catalase activities were found to be decreased in birds sampled from the contaminated site when compared to less polluted areas. The population of sparrows feeding in Ghannouche had enhanced renal thiobarbituric acid reactive substance levels, indicating oxidative damage to membrane lipids. Some histopathological alterations were also observed including kidney interstitial dilatations. Overall, our findings demonstrated that the exposure to pollutants released by the factory complex possessed nephrotoxic by depleting renal antioxidant defense system and promoting kidney morphometric damage in sparrows. These results constitute an early warning of an ecological change in relation to human health.

Effect of garlic on rats with chronic intermittent hypoxia combined with diabetes mellitus.

The present study investigated the effect of garlic (G) on serum, liver, renal and cerebral parameters of rats with chronic intermittent hypoxia (CIH) combined with diabetes mellitus (DM). A total of 32 rats were divided into eight groups, with 4 rats/group. A total of three models were established, including CIH, DM and CIH‑DM, and an additional healthy control (C) group. Rats in C‑G, CIH‑G, DM‑G and CIH‑DM‑G groups were injected with a G extract daily. Serum, liver, renal and cerebral parameters were detected. The results demonstrated that the rats' weight increased gradually, but at a slower rate in the CIH, DM and CIH‑DM groups compared with the healthy rats. Blood glucose increased in the DM and CIH‑DM groups compared with the healthy control group, while insulin level increased in the CIH group, but decreased in the DM and CIH‑DM groups, resulting in increased homeostatic model assessment of insulin resistance (HOMA‑IR) value in the CIH group, compared with healthy controls. Serum thiobarbituric acid reactive substances (TBARS), glutathione S‑transferase (GST), uric acid (UA), urine protein (UP), total cholesterol (TC), triglycerides (TG), total lipids (TL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP) and acid phosphatase (ACP) increased in the CIH, DM and CIH‑DM groups, while albumin and superoxide dismutase (SOD) decreased in all model groups compared with healthy controls. Nitric oxide (NO) increased in the DM and CIH‑DM groups but decreased in the CIH group, compared with the control group. Glutathione peroxidase (GSH‑Px) increased in the CIH group but decreased in the DM and CIH‑DM groups, compared with the control group. Glutathione reductase (GR) increased in the DM group but decreased in the CIH and CIH‑DM groups, compared with the control group. Liver TBARS and GST increased, while AST, ALT, LDH, ALP, ACP, catalase activity (CAT) and SOD decreased in the CIH, DM and CIH‑DM groups, compared with the control group. Liver GSH‑Px decreased in the DM and CIH‑DM groups, compared with the control group. Renal TBARS in the DM and CIH‑DM groups increased compared with the control group. Renal GST increased while CAT and SOD decreased in the CIH, DM and CIH‑DM groups, compared with the control group. Cerebral TBARS increased in the CIH, DM and CIH‑DM groups and LDH increased in the DM and CIH‑DM groups, compared with the control group. Cerebral LDH in CIH decreased compared with the control group. G treatment improved weight gain, blood insulin and HOMA‑IR in the DM and CIH‑DM groups, reduced blood glucose in the DM and CIH‑DM groups, and insulin and HOMA‑IR in the CIH group, compared with the respective G‑untreated groups. G treatment increased serum SOD in CIH‑G, DM‑G and CIH‑DM‑G groups, GSH‑Px and albumin in the DM‑G and CIH‑DM‑G groups, and GR in the DM‑G group, compared with the respective G‑untreated groups. G treatment decreased serum TBARS, UA, UP, TC, TG, TL, AST, ALT, LDH and ACP in the CIH‑G, DM‑G and CIH‑DM‑G groups; NO in the DM‑G group; GST and GR in the CIH‑G and CIH‑DM‑G groups; and ALP in the DM‑G and CIH‑DM‑G groups, compared with the respective G‑untreated groups. Liver AST, ALT, LDH, ALP, CAT, SOD in the CIH‑G, DM‑G and CIH‑DM‑G groups increased as a result of G treatment. GSH‑Px increased in the DM‑G and CIH‑DM‑G groups, ACP in the CIH‑G and DM‑G groups, renal CAT in the CIH‑DM‑G group, and renal SOD in the CIH‑G and CIH‑DM‑G groups, compared with the respective G‑untreated groups. Liver and cerebral TBARS decreased in all G‑treated experimental groups, and liver and renal GST, and cerebral LDH decreased in the DM‑G and CIH‑DM‑G groups, compared with the respective G‑untreated groups. The present study concluded that G aided in the recovery of homeostasis and metabolism in rats with CIH combined with DM, and protected rats' organs from damage induced by CIH combined with DM.

QiShenYiQi Pills, a Compound Chinese Medicine, Prevented Cisplatin Induced Acute Kidney Injury via Regulating Mitochondrial Function.

Nephrotoxicity is a serious adverse effect of cisplatin chemotherapy that limits its clinical application, to deal with which no effective management is available so far. The present study was to investigate the potential protective effect of QiShenYiQi Pills (QSYQ), a compound Chinese medicine, against cisplatin induced nephrotoxicity in mice. Pretreatment with QSYQ significantly attenuated the cisplatin induced increase in plasma urea and creatinine, along with the histological damage, such as tubular necrosis, protein cast, and desquamation of epithelial cells, improved the renal microcirculation disturbance as indicated by renal blood flow, microvascular flow velocity, and the number of adherent leukocytes. Additionally, QSYQ prevented mitochondrial dysfunction by preventing the cisplatin induced downregulation of mitochondrial complex activity and the expression of NDUFA10, ATP5D, and Sirt3. Meanwhile, the cisplatin-increased renal thiobarbituric acid-reactive substances, caspase9, cleaved-caspase9, and cleaved-caspase3 were all diminished by QSYQ pretreatment. In summary, the pretreatment with QSYQ remarkably ameliorated the cisplatin induced nephrotoxicity in mice, possibly via the regulation of mitochondrial function, oxidative stress, and apoptosis.

Renoprotective effect of virgin coconut oil in heated palm oil diet-induced hypertensive rats.

Virgin coconut oil, rich in antioxidants, was shown to attenuate hypertension. This study aimed to investigate the effects of virgin coconut oil on blood pressure and related parameters in kidneys in rats fed with 5-times-heated palm oil (5HPO). Thirty-two male Sprague-Dawley rats were divided into 4 groups. Two groups were fed 5HPO (15%) diet and the second group was also given virgin coconut oil (1.42 mL/kg, oral) daily for 16 weeks. The other 2 groups were given basal diet without (control) and with virgin coconut oil. Systolic blood pressure was measured pre- and post-treatment. After 16 weeks, the rats were sacrificed and kidneys were harvested. Dietary 5HPO increased blood pressure, renal thiobarbituric acid reactive substance (TBARS), and nitric oxide contents, but decreased heme oxygenase activity. Virgin coconut oil prevented increase in 5HPO-induced blood pressure and renal nitric oxide content as well as the decrease in renal heme oxygenase activity. The virgin coconut oil also reduced the elevation of renal TBARS induced by the heated oil. However, neither dietary 5HPO nor virgin coconut oil affected renal histomorphometry. In conclusion, virgin coconut oil has a potential to reduce the development of hypertension and renal injury induced by dietary heated oil, possibly via its antioxidant protective effects on the kidneys.

Beneficial effects of nilotinib, tyrosine kinase inhibitor on cyclosporine-A induced renal damage in rats

Nilotinib is a known tyrosine kinase inhibitor that has been approved for treatment of leukemia. The possible protective effect of nilotinib on cyclosporine A-induced nephropathy was investigated in this study and the possible underlying mechanism was explored. Nilotinib (25mg/kg, orally) and cyclosporine A (15mg/kg/day, subcutaneous) were given to male SD rats for 28days. Cyclosporine A alone was found to significantly increase serum creatinine, blood urea nitrogen, lactate dehydrogenase, urinary micrototal protein, renal thiobarbituric acid reactive substance, Bax, cytosol cytochrome c release and nuclear factor kappa B activation. Moreover, cyclosporine A significantly reduced serum albumin, creatinine clearance, urinary total antioxidant, superoxide dismutase, glutathione and Bcl2 protein levels. Pathological results showed that in the model group; there was an obvious shrinkage and congestion of the glomeruli and widening of urinary spaces of renal corpuscles, in addition to marked renal tubular injury and fibrosis, while in the group pretreated with nilotinib all measured serum, renal and pathological changes were significantly reduced. This protective effect of nilotinib is linked to the enhanced antioxidant status and reduced inflammation and apoptosis induced by cyclosporine A.

RENOPROTECTIVE EFFECTS OF THYMOQUINONE AGAINST CISPLATIN-INDUCED NEPHROTOXICITY IN RATS

Background: Cisplatin (CIS) is one of the most effective chemotherapeutic agents and is used to treat various types of tumors. However its optimal clinical benefit is limited by its serious nephrotoxicity. Objective: Investigating the possible effects of thymoquinone (TQ), a compound derived from Nigella sativa with strong anti-oxidant properties, against CIS-induced nephrotoxicity. Materials and Methods: Forty adult male albino rats were divided into four equal groups: Rats in the first group were injected daily with normal saline, rats in the second group received TQ, rats in the third group were injected with CIS on the sixth day of experiment, whereas rats in the fourth group received TQ in drinking water for 11 consecutive days in addition to CIS injection (7.5 mg/kg, i.p.) on the sixth day of experiment. The animal were sacrificed at day 12 and following parameters were evaluated: (i) the levels of serum creatinine (Cr) and the blood urea nitrogen (BUN) as biomarkers of renal function, (ii) the renal content of thiobarbituric acid reactive substances (TBARS) as an index of lipid perioxidation and oxidative stress, (iii) total glutathione (GSH) content and glutathione S-transferase (GST) activity in renal tissues as indices of antioxidant mechanisms, and (iv) the histopathological hallmarks of kidney specimens. Results: CIS administration induced nephrotoxicity associated with significant higher in the levels of serum Cr, BUN, and renal TBARS and significant reductions in the renal GSH and GST. The histopathological findings supported the presence of seriously injured kidney. However, administration of TQ efficiently reduced the development of CIS nephrotoxicity and its associated biochemical and histopathological features. Conclusion: TQ mediates via, at least in part its antioxidant property, a marked renoprotective effect against CIS-induced nephrotoxicity.

Change in soluble epoxide hydrolase (sEH) during cisplatin-induced acute renal failure in mice.

Cisplatin is one of the most effective chemotherapeutic agents against various types of cancers; however, it is also associated with nephrotoxicity. Recently, it was reported that inflammatory mechanisms play a key role in the development of nephrotoxicity. Epoxyeicosatrienoic acids (EETs) have an anti-inflammatory effect and are metabolized by soluble epoxide hydrolase (sEH: encoded by EPHX2 gene). Here, we determined the change in sEH activity and EPHX2 expression in renal tissue associated with the development of cisplatin-induced nephrotoxicity. Cisplatin administration decreased hydrolase activity accompanied by down-regulation of sEH and EPHX2 expression. The down-regulation occurred prior to the elevation of blood urea nitrogen (BUN) and tumor necrosis factor-α (TNF-α) gene expression or at treatment with low dose cisplatin. In addition, a negative correlation was found between EPHX2 expression and renal thiobarbituric acid reactive substance (TBARS), and edaravone, a radical scavenger, administration did not down-regulate expression of this gene. The results of this study suggest that cisplatin decreased sEH activity through the down-regulation of sEH and EPHX2 expression, and this down-regulation was involved in a negative feedback loop to protect renal tissue from further damage. Thus, sEH is a potential therapeutic target of cisplatin-induced nephrotoxicity.

Betaine supplementation mitigates cisplatin-induced nephrotoxicity by abrogation of oxidative/nitrosative stress and suppression of inflammation and apoptosis in rats

Cisplatin is one of the most potent chemotherapeutic antitumor drugs used in the treatment of a wide range of solid tumors. Its primary dose-limiting side effect is nephrotoxicity. This study aims to investigate the effect of betaine supplementation on cisplatin-induced nephrotoxicity. A single intraperitoneal injection of cisplatin (5mg/kg) deteriorated the kidney functions as reflected by elevated blood urea nitrogen and serum creatinine levels. Oxidative/nitrosative stress was evident in cisplatin group by increased renal thiobarbituric acid-reactive substances (TBARS), an indicator of lipid peroxidation, reduced renal total antioxidant status and increased renal nitrite concentration. Cisplatin resulted in a decline in the concentrations of reduced glutathione, glutathione peroxidase, catalase, and superoxide dismutase in renal tissues. Renal tumor necrosis factor-α (TNF-α) was also elevated. Expressions of nuclear factor-kappa B (NF-κB) and caspase-3 were up-regulated in renal tissues as indicated by immunohistochemical analysis. Histopathological changes were observed in cisplatin group. Betaine supplementation (250mg/kg/day) orally via gavage for 21 days prior to cisplatin injection was able to protect against deterioration in kidney function, abrogate the decline in antioxidants enzymes and suppressed the increase in TBARS, nitrite and TNF-α concentrations. Moreover, betaine inhibited NF-κB and caspase-3 activation and improved the histological changes induced by cisplatin. Thus, the present study demonstrated the renoprotective nature of betaine by attenuating the pro-inflammatory and apoptotic mediators and improving antioxidant competence in kidney tissues of cisplatin treated rats. Betaine could be a beneficial dietary supplement to attenuate cisplatin nephrotoxicity.

H2S donors attenuate diabetic nephropathy in rats: Modulation of oxidant status and polyol pathway

BackgroundSulfurous mineral water and its main active ingredient sodium hydrosulfide (NaHS) are major sources of H2S. The present study aimed to explore their protective effect on one of the serious long-term complications of diabetes; diabetic nephropathy. MethodsSulfurous mineral water (as drinking water), NaHS (14μmol/kg/day; ip), and gliclazide (10mg/kg; po) were administered daily for 6 weeks to streptozotocin (STZ)-diabetic rats. ResultsSTZ-induced diabetes was associated with body weight reduction, hyperglycemia, overproduction of glycated hemoglobin, as well as decline in serum insulin, C-peptide, and insulin like growth factor-I. Besides, diabetes impaired kidney functions and imposed oxidative and nitrosative stress as manifested by elevated contents of renal thiobarbituric acid reactive substances and nitric oxide, parallel to reduced glutathione content. These deleterious effects were antagonized by sulfurous water and to a better extent by NaHS. Activities of myeloperoxidase and sorbitol dehydrogenase were not altered by STZ or any of the treatments. However, STZ-induced diabetes was accompanied by an increment of aldose reductase which was only mitigated by gliclazide and NaHS. Histopathological examination of kidney sections corroborated the biochemical findings. ConclusionThis study suggests a novel therapeutic approach for diabetic nephropathy using H2S donors.

Protective effect of Ferula gummosa hydroalcoholic extract against nitric oxide deficiency-induced oxidative stress and inflammation in rats renal tissues

Nitric oxide (NO) synthase inhibition increases hypertension and causes renal injury. Ferula gummosa is used in Iranian traditional medicine for treatment of several diseases and has been reported to exert a potent anti-inflammatory and antioxidant action. The aim of this investigation was to evaluate the renoprotective effects of hydroalcoholic extract of Ferula gummosa (HEG) on Nω-nitro-l-arginine methyl ester (l-NAME)-induced oxidative stress and inflammation and explore the mechanisms that link NO deficiency with altered renal heat shock protein (HSP70). Rats were injected intraperitoneally with l-NAME (10 mg/kg) to induce renal injury. Simultaneously, HEG (90 mg/kg) was administered by gastric gavage to l-NAME-treated rats for 6 days/week during an 8-week period. Renal thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), HSP70, plasma NO and total antioxidant capacity (TAC) were evaluated. The administration of l-NAME significantly increased renal TBARS, TNF-α, IL-6, HSP70 levels and decreased renal SOD activity, that these changes were accompanied by the reduced plasma NO and TAC levels. HEG administration decreased TBARS, HSP70, TNF-α and IL-6 levels and increased SOD activity in the kidney tissues of l-NAME treated rats (p < 0.05). Also, plasma TAC level and NO bioavailability have been elevated after administration of HEG (p < 0.05). These findings support that NO deficiency induces renal stress oxidative and inflammation, which markedly increased renal HSP70 and HEG could protect kidney against these damaging effects via its anti-oxidative, anti-inflammatory action and modulate renal HSP70.

5-Aminolevulinic acid combined with ferrous iron induces carbon monoxide generation in mouse kidneys and protects from renal ischemia-reperfusion injury

Renal ischemia reperfusion injury (IRI) is a major factor responsible for acute renal failure. An intermediate in heme synthesis, 5-aminolevulinic acid (5-ALA) is fundamental in aerobic energy metabolism. Heme oxygenase (HO)-1 cleaves heme to form biliverdin, carbon monoxide (CO), and iron (Fe(2+)), which is used with 5-ALA. In the present study, we investigated the role of 5-ALA in the attenuation of acute renal IRI using a mouse model. Male Balb/c mice received 30 mg/kg 5-ALA with Fe(2+) 48, 24, and 2 h before IRI and were subsequently subjected to bilateral renal pedicle occlusion for 45 min. The endogenous CO concentration of the kidneys from the mice administered 5-ALA/Fe(2+) increased significantly, and the peak concentrations of serum creatinine and blood urea nitrogen decreased. 5-ALA/Fe(2+) treatments significantly decreased the tubular damage and number of apoptotic cells. IRI-induced renal thiobarbituric acid-reactive substance levels were also significantly decreased in the 5-ALA/Fe(2+) group. Furthermore, mRNA expression of HO-1, TNF-α, and interferon-γ was significantly increased after IRI. Levels of HO-1 were increased and levels of TNF-α and interferon-γ were decreased in the 5-ALA/Fe(2+)-pretreated renal parenchyma after IRI. F4/80 staining showed reduced macrophage infiltration, and TUNEL staining revealed that there were fewer interstitial apoptotic cells. These findings suggest that 5-ALA/Fe(2+) can protect the kidneys against IRI by reducing macrophage infiltration and decreasing renal cell apoptosis via the generation of CO.

Boldine Prevents Renal Alterations in Diabetic Rats

Diabetic nephropathy alters both structure and function of the kidney. These alterations are associated with increased levels of reactive oxygen species, matrix proteins, and proinflammatory molecules. Inflammation decreases gap junctional communication and increases hemichannel activity leading to increased membrane permeability and altering tissue homeostasis. Since current treatments for diabetic nephropathy do not prevent renal damage, we postulated an alternative treatment with boldine, an alkaloid obtained from boldo with antioxidant, anti-inflammatory, and hypoglycemic effects. Streptozotocin-induced diabetic and control rats were treated or not treated with boldine (50 mg/Kg/day) for ten weeks. In addition, mesangial cells were cultured under control conditions or in high glucose concentration plus proinflammatory cytokines, with or without boldine (100 µmol/L). Boldine treatment in diabetic animals prevented the increase in glycemia, blood pressure, renal thiobarbituric acid reactive substances and the urinary protein/creatinine ratio. Boldine also reduced alterations in matrix proteins and markers of renal damage. In mesangial cells, boldine prevented the increase in oxidative stress, the decrease in gap junctional communication, and the increase in cell permeability due to connexin hemichannel activity induced by high glucose and proinflammatory cytokines but did not block gap junction channels. Thus boldine prevented both renal and cellular alterations and could be useful for preventing tissue damage in diabetic subjects.