Oxidative Stress In Renal Tissues Research Articles

Doxorubicin-induced alterations in kidney functioning, oxidative stress, DNA damage, and renal tissue morphology; Improvement by Acacia hydaspica tannin-rich ethyl acetate fraction.

Doxorubicin (DOX) is an anthracycline drug used for cancer treatment. However, its treatment is contiguous with toxic effects. We examined the nephroprotective potential of A. hydaspica polyphenol-rich ethyl acetate extract (AHE) against DOX persuaded nephrotoxicity. 36 male Sprague Dawley rats were randomly assorted into 6 groups. Control group received saline; DOX group: 3 mg/kg b.w. dosage of DOX intraperitoneally for 6 weeks (single dose/week). In co-treatment groups, 200 and 400 mg/kg b.w AHE was given orally for 6 weeks in concomitant with DOX (3 mg/kg b.w, i.p. injection per week) respectively. Standard group received silymarin 400 mg/kg b.w daily + DOX (single dose/week). Biochemical kidney function tests, oxidative stress markers, genotoxicity, antioxidant enzyme status, and histopathological changes were examined. DOX caused significant body weight loss and decrease kidney weight. DOX-induced marked deterioration in renal function indicators in both urine and serum, i.e., PH, specific gravity, total protein, albumin, urea, creatinine, uric acid, globulin, blood urea nitrogen, etc. Also, DOX treatment increases renal tissue oxidative stress markers, while lower antioxidant enzymes in tissue along with degenerative alterations in the renal tissue compared to control rats. AHE co-treatment ameliorates DOX-prompted changes in serum and urine chemistry. Likewise, AHE treatment decreases sensitive markers of oxidative stress and prevented DNA damages by enhancing antioxidant enzyme levels. DOX induction in rats also caused DNA fragmentation which was restored by AHE co-treatment. Moreover, the histological observations evidenced that AHE effectively rescued the kidney tissue from DOX interceded oxidative damage. Our results suggest that co-treatment of AHE markedly improve DOX-induced deleterious effects in a dose-dependent manner. The potency of AHE co-treatment at 400 mg/kg dose is similar to silymarin. These outcomes revealed that A. hydaspica AHE extract might serve as a potential adjuvant that avoids DOX-induced nephrotoxicity.

Effects of Sodium\u2013Glucose Co-transporter 2 Inhibition with Empaglifozin on Renal Structure and Function in Non-diabetic Rats with Left Ventricular Dysfunction After Myocardial Infarction

BackgroundThe use of sodium–glucose co-transporter 2 inhibitors (SGLT2i) is currently expanding to cardiovascular risk reduction in non-diabetic subjects, but renal (side-)effects are less well studied in this setting.MethodsMale non-diabetic Sprague Dawley rats underwent permanent coronary artery ligation to induce MI, or sham surgery. Rats received chow containing empagliflozin (EMPA) (30 mg/kg/day) or control chow. Renal function and electrolyte balance were measured in metabolic cages. Histological and molecular markers of kidney injury, parameters of phosphate homeostasis and bone resorption were also assessed.ResultsEMPA resulted in a twofold increase in diuresis, without evidence for plasma volume contraction or impediments in renal function in both sham and MI animals. EMPA increased plasma magnesium levels, while the levels of glucose and other major electrolytes were comparable among the groups. Urinary protein excretion was similar in all treatment groups and no histomorphological alterations were identified in the kidney. Accordingly, molecular markers for cellular injury, fibrosis, inflammation and oxidative stress in renal tissue were comparable between groups. EMPA resulted in a slight increase in circulating phosphate and PTH levels without activating FGF23–Klotho axis in the kidney and bone mineral resorption, measured with CTX-1, was not increased.ConclusionsEMPA exerts profound diuretic effects without compromising renal structure and function or causing significant electrolyte imbalance in a non-diabetic setting. The slight increase in circulating phosphate and PTH after EMPA treatment was not associated with evidence for increased bone mineral resorption suggesting that EMPA does not affect bone health.

The protective effect of hesperidin against renal ischemia-reperfusion injury involves the TLR-4/NF-κB/iNOS pathway in rats.

Renal injury is reported to have a high mortality rate. Additionally, there are several limitations to current conventional treatments that are used to manage it. This study evaluated the protective effect of hesperidin against ischemia/reperfusion (I/R)-induced kidney injury in rats. Renal injury was induced by generating I/R in kidney tissues. Rats were then treated with hesperidin at a dose of 10 or 20 mg/kg intravenously 1 day after surgery for a period of 14 days. The effect of hesperidin on renal function, serum mediators of inflammation, and levels of oxidative stress in renal tissues were observed in rat kidney tissues after I/R-induced kidney injury. Moreover, protein expression and mRNA expression in kidney tissues were determined using Western blotting and RT-PCR. Hematoxylin and eosin (H&E) staining was done for histopathological observation of kidney tissues. The data suggest that the levels of blood urea nitrogen (BUN) and creatinine in the serum of hesperidin-treated rats were lower than in the I/R group. Treatment with hesperidin also ameliorated the altered level of inflammatory mediators and oxidative stress in I/R-induced renal-injured rats. The expression of p-IκBα, caspase-3, NF-κB p65, Toll-like receptor 4 (TLR-4) protein, TLR-4 mRNA, and inducible nitric oxide synthase (iNOS) was significantly reduced in the renal tissues of hesperidin-treated rats. Histopathological findings also revealed that treatment with hesperidin attenuated the renal injury in I/R kidney-injured rats. In conclusion, our results suggest that hesperidin protects against renal injury induced by I/R by involving TLR-4/NF-κB/iNOS signaling.

Ameliorative Effect of Propolis Against Thioacetamide Induced Hepatorenal Injury in Adult Male Rats. Kidney Injury Molecule-1 (KIM-1) a Biomarker of Renal Injury

Abstract Background: Thioacetamide (TAA), a known industrial toxic agent, is extensively used in animal studies for induction of hepatic necrosis, fibrosis and cirrhosis, also reported to be nephrotoxic through induction of oxidative stress. Propolis, bee glue, is known by its antioxidant and anti-inflammatory properties. Aim of Study: This work aimed to evaluate the potential protective effect of propolis on TAA-induced hepatorenal damage and to evaluate the efficacy of Kidney Injury Molecuole-1 (KIM-1) in early detection of renal injury. Material and Methods: This study was performed on 24 adult male albino rats, divided into 3 groups; (I) Control group, (II) TAA-group (TAA was given in a dose of 50mg/kg /day intraperitoneally, 5 days/week for 2 weeks), (III) TAA-propolis treated group (TAA was given in the same way as in TAA-group, propolis was given in a dose of 500mg/kg/day by gavage, 5 days/week for 2 weeks). All studied rats were subjected to determination of initial and final body weight, body weight percent change, absolute and relative liver and kidney weight, as well as assessment of hepatic function by serum Alanine Transaminase (ALT) and Aspartate Transam-inase (AST), renal function by serum urea, creatinine and potassium (K+) level, with determination of renal tissue oxidative stress markers; Malondialdehyde (MDA) and Glu-tathione-S-Transferase (GST), inflammatory marker; Mye-loperoxidase (MPO), renal tissue damage marker; Kidney Injury Molecule-1 (KIM-1). In addition, specimens of liver and kidney were taken and processed for light microscopic studies. Results: TAA induced hepatotoxic and nephrotoxic effect that was evident by the significantly increased serum ALT, AST, urea and creatinine, with significant decrease in serum K+ level as well as significantly increased renal tissue MDA, GST, MPO and KIM-1 when compared with control group. Treatment with propolis caused significant reduction in serum ALT, AST, urea and creatinine, with significant elevation in serum K+ as well as significant reduction in renal tissue MDA, GST, MPO and KIM-1 when compared to the TAA group, but still significantly higher compared to controls except for urea. These results were confirmed by the histopathological findings. Conclusion: Propolis could partially ameliorate the TAA induced hepatorenal damage, which might be related to attenuation of oxidative stress and inflammation. Moreover, KIM-1 could be beneficial in detection of renal injury.

Sinapic acid attenuates cisplatin-induced nephrotoxicity through peroxisome proliferator-activated receptor gamma agonism in rats.

ABSTRACTAim:The aim of this study was to investigate the involvement of peroxisome proliferator-activated receptor gamma (PPAR-γ) in renal protection offered by sinapic acid in cisplatin-induced nephrotoxicity in male rats.Materials and Methods:Nephrotoxicity was induced by single dose of cisplatin (5 mg/kg, intraperitoneal [i.p.]) in rats. Cisplatin-induced nephrotoxicity was assessed by measuring serum creatinine, creatinine clearance, urea, uric acid, potassium, magnesium levels, fractional excretion of sodium, and microproteinuria in rats. Superoxide anion generation, thiobarbituric acid reactive substances, myeloperoxidase activity, and reduced glutathione levels were measured to assess oxidative stress in renal tissues. Hematoxylin and eosin stain showed renal histological changes.Results:The significant changes in serum and urinary parameters, elevated oxidative stress, and renal histological changes established the induction of nephrotoxicity. Sinapic acid treatment (20 and 40 mg/kg, orally [p.o.]) provides dose-dependent and significant (P < 0.05) nephroprotection against cisplatin-mediated nephrotoxicity in rats. Nephroprotective effect of sinapic acid was abolished by PPAR-γ inhibitor, bisphenol A diglycidyl ether (30 mg/kg, i.p.) in rats.Conclusion:It is concluded that PPAR-γ agonism serves as one of the mechanisms in sinapic acid-mediated renoprotection.

Nephroprotective effect of melatonin and L-Ascorbic acid (Vitamin-C) against ampicillin- induced toxicity in Funambulus pennanti

ABSTRACT Ampicillin is one of the most commonly prescribed antibiotics against intra-renal infections. Prolonged use of ampicillin has been found to be associated with a high rate of free-radical generation and oxidative stress induced nephrotoxicity. In the present study, we report the comparative effects of melatonin and vitamin-C (Vit-C) in ameliorating the biochemical and structural alterations in renal tissues caused by ampicillin sodium. Biochemical parameters such as acid phosphatase (ACP), alkaline phosphatase (ALP), creatinine and urea levels in urine and serum as well as oxidative stress parameters such as superoxide dismutase (SOD) activity, catalase activity, total antioxidant status (TAS%) and lipid peroxidation in the renal cortical tissues were accessed upon treatment of melatonin and Vit-C following ampicillin sodium administration in Funambulus pennanti. Ampicillin treatment increased ACP, ALP, creatinine and urea levels in serum and urine, indicating renal damage. It also induced oxidative stress by increasing lipid peroxidation and decreasing the activity of antioxidative enzymes. However, the exogenous melatonin or Vit-C treatment inhibited ampicillin mediated renal damages. Melatonin or Vit-C pre-treatment significantly decreased ACP, ALP, creatinine, urea, TBARS level and increased SOD, catalase activity and TAS%. Our results suggest that the antibiotic induced nephrotoxicity can be ameliorated by melatonin or Vit-C via reduction of oxidative stress in renal tissues.

The oral hypoxia-inducible factor prolyl hydroxylase inhibitor enarodustat counteracts alterations in renal energy metabolism in the early stages of diabetic kidney disease

Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors, also known as HIF stabilizers, increase endogenous erythropoietin production and serve as novel therapeutic agents against anemia in chronic kidney disease. HIF induces the expression of various genes related to energy metabolism as an adaptive response to hypoxia. However, it remains obscure how the metabolic reprogramming in renal tissue by HIF stabilization affects the pathophysiology of kidney diseases. Previous studies suggest that systemic metabolic disorders such as hyperglycemia and dyslipidemia cause alterations of renal metabolism, leading to renal dysfunction including diabetic kidney disease. Here, we analyze the effects of enarodustat (JTZ-951), an oral HIF stabilizer, on renal energy metabolism in the early stages of diabetic kidney disease, using streptozotocin-induced diabetic rats and alloxan-induced diabetic mice. Transcriptome analysis revealed that enarodustat counteracts the alterations in diabetic renal metabolism. Transcriptome analysis showed that fatty acid and amino acid metabolisms were upregulated in diabetic renal tissue and downregulated by enarodustat, whereas glucose metabolism was upregulated. These symmetric changes were confirmed by metabolome analysis. Whereas glycolysis and tricarboxylic acid cycle metabolites were accumulated and amino acids reduced in renal tissue of diabetic animals, these metabolic disturbances were mitigated by enarodustat. Furthermore, enarodustat increased the glutathione to glutathione disulfide ratio and relieved oxidative stress in renal tissue of diabetic animals. Thus, HIF stabilization counteracts alterations in renal energy metabolism occurring in incipient diabetic kidney disease.

Effects of single and dual RAAS blockade therapy on progressive kidney disease transition to CKD in rats.

Ischemic reperfusion (I/R) is the primary cause of acute kidney injury (AKI) in hospitalized patients. Although AKI resolution occurs in few days, it predisposes kidneys to progressive renal injury. Previously, administration of rennin-angiotensin-aldosterone system (RAAS) blocker spironolactone in acute phase was reported to attenuate various manifestations of chronic kidney disease (CKD) in rats. The present study investigates the effects of RAAS blockade during progressive kidney disease (30 days onwards) on CKD outcomes in rodent model of I/R injury. CKD was induced by clamping both renal pedicles for 45 min followed by 90 days of reperfusion in rats. Single and dual RAAS blocker therapy was initiated at 30 days post-I/R injury and continued until the end of the study period. Evaluation of proteinuria and creatinine levels was done every 30 days in various study groups. Assessment of CKD was done by analyzing renal tissue oxidative stress, inflammatory biomarker levels, and histological changes after 90 days of I/R injury. After 90 days, I/R rat kidneys displayed hypertrophy, reduced body weight, increased oxidative stress, elevated inflammatory biomarker levels, and histological abnormalities such as glomerulosclerosis, mesangial expansion, and tubulointerstitial fibrosis. Treatment with losartan or spironolactone alone significantly reduced various CKD-associated features. Remarkably, combined treatment with dual RAAS blocker in low dose or high dose exhibited highest beneficial effects on various parameters in CKD model, with low-dose combination showing fewer side effects. Therefore, we propose that combined low-dose RAAS blockade therapy might serve as a better therapeutic approach for retarding progressive kidney disease transition to CKD.

The Protective Effects of Thymosin-β-4 in a Rat Model of Ischemic Acute Kidney Injury

Background Despite the progress in the treatment of acute kidney injury (AKI), current curative approaches fail to provide adequate treatment. In this study, we aimed to investigate the possible protective effects of thymosin-β-4(Tβ4) on an ischemic AKI model in rats. Methods Rats were randomly assigned into four groups (n = 8/group): The control group (sham-operated), the ischemia-reperfusion (I/R) group; renal ischemia (90 min) by infrarenal abdominal aortic occlusion followed by reperfusion (3 h), the Tβ4 + I/R group; treated with Tβ4 before I/R, and the I/Tβ4/R group; treated with Tβ4 just before reperfusion. Besides renal function determination (creatinine (Cr) and blood urea nitrogen (BUN)); histological evaluation was also conducted. Renal tissue caspase-9, matrix metalloproteinase (MMP-9) activities, and hyaluronan levels were measured. Additionally, renal tissue oxidative stress (lipid hydroperoxide, malondialdehyde, superoxide dismutase, glutathione, pro-oxidant-antioxidant balance, ferric reducing antioxidant power, nitric oxide), inflammation (tumor necrosis factor-α, interleukin-1β, interleukin-6, nuclear factor-κβ) were evaluated. Results I/R increased the level of caspase-9, MMP-9 activity, and hyaluronan (p < 0.001) and these were significantly decreased in both Tβ4 groups. Moreover, I/R led to increases in oxidative stress and inflammation parameters (p < 0.001) while the levels of antioxidants were decreased. Nevertheless, Tβ4 in both groups were able to restore oxidative stress and inflammation parameters. Furthermore, Tβ4 attenuated histologic injury caused by I/R (p < 0.01) and diminished serum urea-creatinine levels (p < 0.001). Conclusion These results suggest that Tβ4 has significant improving effects in ischemic acute kidney injury. This beneficial effect might be a result of the inhibition of extracellular matrix remodeling and apoptosis cascade via modulation in renal redox status and inflammation.

Positive Role of Dynamic Resistance Training in the Management of Renal Oxidative Stress in Female Hypertensive Rats

Hypertension (HA) is associated with important renal dysfunctions, being one of the main causes of chronic kidney disease. It is well known that oxidative stress plays a fundamental role in the pathophysiology of hypertension and of chronic kidney disease. On the other hand, aerobic physical training is recommended in the management of hypertension and CKD. Moreover, dynamic resistance training has been recommended as a complement to aerobic, however few studies have explored the influence of this type of training on oxidative stress markers in hypertensive females. In this sense, the objective of the present study was to evaluate the effects of dynamic resistance training (DRT) of moderate intensity on physical capacity, hemodynamic parameters and renal oxidative stress profile in female spontaneously hypertensive rats. Sixteen female spontaneously hypertensive rats (SHR, 3 months old) were distributed into 2 groups (n=8/group): sedentary (SF) and trained (TF). The TF group underwent 8 weeks of DRT on adapted ladder (40–60% of the maximal load test). At the end of the training, physical capacity, blood pressure (BP), heart rate (HR) and oxidative stress in renal tissue were evaluated. As a result, the maximum load of the TF group was increased in relation to SF (485.43±25.03 vs. 403.62±28.51 g) and body weight increase in both groups during the protocol (p &lt;0.05). There was no difference in BP (mean BP‐ SF:173±6.8 vs. TF: 172±5.7 mmHg) and HR (SF: 379±11 vs. TF: 370±11 bpm) between the groups. In the oxidative stress parameters, there was a decrease in protein oxidation (4.84±0.14 vs. 5.72±0.38 nmol/mg protein) and in lipoperoxidation (1475±218 vs. 2680±351 cps/mg protein) in the TF compared to SF group. Regarding antioxidant enzymes, there was no difference in superoxide dismutase and glutathione peroxidase, but there was a decrease in the activity of the catalasein the TF in relation SF group (3.5±0.2 vs. 4.2±0.2 nmol/mg protein). In addition, there was no difference between groups in NADPH oxidase activity (0.18±0.01 vs. 0.22±0.02 μmol/mg protein) and superoxide anion concentration (1.56±0.04 vs. 1.91±0.05 O2.‐ mmol/mg protein). However, there was a reduction in hydrogen peroxide in the TF in relation to SF group (10.54±1.99 vs. 21.98±1.85 nmol H2O2). There was a positive correlation between catalase and hydrogen peroxide (r=0.57, p&lt;0.05). In conclusion, moderate‐intensity DRT was a safe approach considering that it did not alter BP. Furthermore, DRT was able to induce strength gain and attenuation of oxidative stress, evidenced by the decrease in pro oxidants (hydrogen peroxide) and markers of tissue damage. Thus, our data reinforces the positive role of DRT in the management of hypertension consequences.Support or Funding InformationCAPES, CNPq, FAPESP 2015/10329‐5This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effect of a novel nonsteroidal selective mineralocorticoid receptor antagonist, esaxerenone (CS-3150), on blood pressure and renal injury in high salt-treated type 2 diabetic mice.

Although beneficial antihypertensive and antialbuminuric effects of steroidal mineralocorticoid receptor (MR) antagonists have been shown, the use of these drugs has been clinically limited in diabetic kidney disease (DKD) because of the high incidence of side effects. Here, we aimed to examine the effect of a novel nonsteroidal selective mineralocorticoid receptor antagonist, esaxerenone, on blood pressure and renal injury in high salt-treated type 2 diabetic KK-Ay mice, a model of human hypertensive DKD. KK-Ay mice were treated with a normal salt diet (NS: 0.3% NaCl, n = 5), high salt diet (HS: 4% NaCl, n = 8), HS + esaxerenone (1 mg/kg/day, p.o., n = 8), or HS + spironolactone, a steroidal non-selective MR antagonist (20 mg/kg/day, p.o., n = 7) for 8 weeks. Renal tissue oxidative stress was evaluated by dihydroethidium florescence intensity. HS-treated diabetic KK-Ay mice showed higher blood pressure and severe albuminuria, glomerular injury, tubulointerstitial fibrosis, renal inflammation, and oxidative stress than NS-treated diabetic KK-Ay mice. Treatment with esaxerenone or spironolactone decreased blood pressure to a similar extent in HS-treated KK-Ay mice. Conversely, esaxerenone elicited a greater attenuation of albuminuria, glomerular injury, tubulointerstitial fibrosis, and renal inflammation than spironolactone, which were associated with reduction in renal oxidative stress. These data indicate for the first time that a nonsteroidal MR antagonist elicits renoprotective effects in DKD mice.

Alleviation of oxidative stress-mediated nephropathy by dietary fenugreek (Trigonella foenum-graecum) seeds and onion (Allium cepa) in streptozotocin-induced diabetic rats.

Oxidative stress plays a major role in the progression of diabetes and the pathogenesis of diabetic nephropathy. In this study, the beneficial influence of dietary fenugreek (Trigonella foenum-graecum) seeds and onion (Allium cepa) on oxidative stress-mediated renal injury was evaluated in streptozotocin-induced diabetic rats. Diabetes was induced in adult Wistar rats by the administration of streptozotocin (i.p. 45 mg kg-1). Dietary interventions were made with 10% fenugreek seeds or 3% onion (freeze-dried) or their combination for 6 weeks. These dietary interventions countered nephromegaly in the diabetic animals, the increase in creatinine clearance and oxidative stress in renal tissue. These dietary interventions significantly countered the increased renal cholesterol and triglycerides associated with the diabetic condition. The up-regulation of the receptor for advanced glycation end products, inflammatory cytokines and oxidative stress markers in the renal tissue of the diabetic rats was effectively countered. Renal 8-hydroxy-2-deoxyguanosine, its excretion, DNA fragmentation and mitochondrial DNA deletion were significantly annulled in the diabetic rats by these dietary interventions. Generally, the beneficial effects were greater in the combined intervention, although they were not additive. Thus, the beneficial influence of dietary fenugreek and onion on oxidative stress-mediated renal injury is higher when consumed together and this may be a strategy to ameliorate diabetic nephropathy.

Betulinic acid, natural pentacyclic triterpenoid prevents arsenic-induced nephrotoxicity in male Wistar rats

The aim of this study was to investigate the possible renoprotective role of betulinic acid, a natural pentacyclic triterpenoid on arsenic-induced nephrotoxicity. Male Wistar rats were divided into four groups and experiment was done as follows: normal control group, arsenic trioxide (4 mg/kg b.wt) group, betulinic acid control (100 mg/kg b.wt) group, and a combination therapy group with both arsenic trioxide (4 mg/kg b.wt) and betulinic acid (100 mg/kg b.wt).The mode of administration of drugs was oral, and duration of study was 30 days. The results showed that the arsenic treatment inflated the urea, uric acid, creatinine, and serum γ-glutamyl tranferase (GGT) in serum and at the same time, creatinine clearance rate was down turned significantly (p < 0.05) in rats. Arsenic-induced oxidative stress in renal tissue was identified by increased levels of lipid peroxidation marker thiobarbituric acid reactive substances (TBARS). Reduced glutathione and enzymatic antioxidants—glutathione S-transferase (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT)—were altered by arsenic exposure. Tubular necrosis and destruction of tubular structures were observed. Betulinic acid treatment markedly attenuated in the arsenic-induced renal tissue damage. These data indicate that the natural antioxidant betulinic acid might have a protective effect against arsenic-induced nephrotoxicity and oxidative stress.

Protective Effect of Exacum lawii on Cisplatin-induced Oxidative Renal Damage in Rats.

Background:Exacum lawii (Gentianaceae), a bitter herb conventionally used in kidney diseases and eye problems, endemic to the Western coast and Southern part of India.Aim:Folklore reports encourage the author to explore the nephroprotective effect of the standardized ethanolic extract of E. lawii against cisplatin-induced renal toxicity in the rat to scientifically validate its traditional use.Materials and Methods:Ethanolic extract of the whole plant of E. lawii was standardized with swertiamarin (secoiridoid glycoside) using high-performance liquid chromatography and tested for subacute toxicity according to the OECD guidelines. Nephroprotective potential at different doses of extract was evaluated against cisplatin (6 mg/kg, intraperitoneal) in experimental rats. The changes in serum renal toxicity markers, renal tissue oxidative stress biomarkers, and proinflammatory cytokines level were measured. To estimate the change in oxidative status of renal tissues, DNA and single viable cells were isolated from treated rat kidney, DNA fragmentation assay and flow cytometric analysis of reactive oxygen species (ROS) were performed. Histopathology of renal tissues was also examined.Results:Swertiamerin was found to be 119.59 mg/g of extract. Administration of E. lawii extract (ELE) restored the biochemical parameters. It also decreases the elevated proinflammatory cytokines level in kidney tissues and protected rat kidneys from oxidative stress in rats. Nephroprotective activity was validated by estimating ROS production in kidney live cells and DNA damage in kidney tissue. The histological architecture was also conserved.Conclusion:ELE showed significant renal protection against cisplatin through reducing oxidative stress and inflammation.SUMMARY High-performance liquid chromatography standardisation of Exacum lawii extract with Swertiamerin and its subacute toxicity studyNephroprotective activity of Exacum lawii extract and Swertiamerin was evaluated in cisplatin-induced model and justified by various biochemical parameters and histopathological studyRole of oxidative stress in cisplatin-induced nephrotoxicity was confirmed by measuring levels of antioxidant markers and proinflammatory cytokines in rat renal tissues, ROS estimation by flow cytometry and DNA fragmentation assay by gel electrophoresis in renal cells. Abbreviations used: ELE: Exacum lawii ethanolic extract; WHO: World Health Organization; SOD: Superoxide dismutase; CAT: Catalase; MDA: Malondialdehyde; HPTLC: High performance thin layer chromatography; p.o.: Per oral; i.p.: Intraperitoneal; TNF-α: Tumor necrosis factor alpha; IL-1β: Interleukin 1 beta; IL-6: Interleukin 6; ROS: Reactive oxygen species.

Protective Effect of Withania coagulans Fruit Extract on Cisplatin-induced Nephrotoxicity in Rats.

Background:Fruits of Withania coagulans (Solanaceae) reported to possess several bioactive compounds as curative agents for various clinical conditions. Cisplatin is a chemotherapeutic drug to treat sarcomas, carcinomas, lymphomas, cervical cancer, germ cell tumors, etc. The major factor that limits its clinical use is its dose-dependent nephrotoxicity.Aim:To explore the nephroprotective effect of W. coagulans extract and its modulatory effects against cisplatin-induced nephrotoxicity and genotoxicity.Materials and Methods:W. coagulans fruit extract was quantitatively standardized with withaferin A using high-performance thin-layer chromatography. The subacute toxicity study was performed according to OECD guidelines in experimental rats. Nephrotoxicity in rats was induced by a single dose of cisplatin (6 mg/kg, intraperitoneal). Nephroprotective role of W. coagulans fruit extract at different doses had been evaluated. It includes quantification of serum kidney toxicity markers, renal tissue oxidative stress biomarkers and pro-inflammatory cytokines level, DNA fragmentation assay, and histopathological examination of renal tissue.Results:Withaferin A was found 3.56 mg/g of W. coagulans fruit extract. It significantly prevented the rise in serum urea and creatinine level and also preserve rat kidneys from oxidative stress and free radical induced DNA damage. Histopathological study showed extract treatment eliminates tubular swelling, cellular necrosis, and protein cast deposition in cisplatin treated kidney tissue. It averted the decline in glutathione content, activities of superoxide dismutase and catalase. These parameters were restored to near normal levels by extract in a dose of 400 mg/kg, per oral. Conclusion: It can be justified that W. coagulans possess dose dependent protective effect against cisplatin induced kidney damages, primarily through its free radical scavenging and anti inflammatory activitySUMMARY Authentication and standardization of Withania coagulans fruitsSubacute oral toxicity studyEvaluation of nephroprotective activity against cisplatin-induced nephrotoxicityDNA fragmentation assay and histopathological examination of kidney tissue in experimental rats. Abbreviations Used: WHO: World Health Organization, SOD: Superoxide dismutase, CAT: Catalase, HPTLC: High-performance thin layer chromatography, p.o.: Per.oral, i.p.: Intraperitoneal, TNF-α: Tumor necrosis factor-alpha, IL-1β: Interleukin 1-beta, IL-6: Interleukin-6

Curcumin alleviates ischemia reperfusion-induced acute kidney injury through NMDA receptor antagonism in rats

Objective: The present study investigated the role of N-methyl-d-aspartate (NMDA) receptors in curcumin-mediated renoprotection against ischemia reperfusion (I/R)-induced acute kidney injury (AKI) in rats.Methods: Rats were subjected to bilateral renal I/R (40 min I, 24 hours R) to induce AKI. Kidney injury was assessed by measuring creatinine clearance, blood urea nitrogen, plasma uric acid, potassium level, fractional excretion of sodium, and macroproteinuria. Oxidative stress in renal tissues was assessed by measuring myeloperoxidase activity, thiobarbituric acid reactive substances, superoxide anion generation, and reduced glutathione content. Hematoxylin & eosin staining was done to assess histological changes in renal tissues. Curcumin (30 and 60 mg/kg) was administered one hour before subjecting rats to AKI. In separate groups, NMDA receptor agonists, glutamic acid (200 mg/kg), and spermidine (20 mg/kg) were administered prior to curcumin treatment in rats followed by AKI.Results: I/R-induced AKI was demonstrated by significant change in plasma and urine parameters along with marked increase in oxidative stress and histological changes in renal tissues that were aggravated with pretreatment of glutamic acid and spermidine in rats. Administration of curcumin resulted in significant protection against AKI. However, glutamic acid and spermidine pretreatments prevented curcumin-mediated renoprotection.Conclusion: It is concluded that NMDA receptor antagonism significantly contributes towards curcumin-mediated protection against I/R-induced AKI.

Pioglitazone ameliorates renal ischemia reperfusion injury through NMDA receptor antagonism in rats.

The present study investigated the role of N-methyl-D-aspartate (NMDA) receptors in pioglitazone-mediated protection against renal ischemia reperfusion injury (IRI) in rats. Male wistar rats were subjected to 40min of bilateral renal ischemia followed by reperfusion for 24h to induce kidney injury. The renal damage was evaluated by measuring serum creatinine, creatinine clearance, blood urea nitrogen, uric acid, electrolytes, and microproteinuria in rats. Oxidative stress in renal tissues was quantified in terms of myeloperoxidase activity, thiobarbituric acid reactive substances, superoxide anion generation, and reduced glutathione level. Hematoxylin-eosin and periodic acid Schiff staining of renal tissues were performed to observe histological changes. Pioglitazone (20 and 40mg/kg) was administered 1h prior to ischemia in rats. In separate groups, NMDA agonists, glutamic acid (200mg/kg), and spermidine (20mg/kg) were administered 1h prior to pioglitazone treatment, followed by renal IRI in rats. Ischemia reperfusion resulted in marked renal damage with significant changes in serum and urine parameters along with marked oxidative stress and histological changes in kidneys. Pioglitazone treatment afforded anti-oxidant effect and renoprotection in a dose-dependent manner in rats. Pioglitazone-mediated renoprotection was attenuated by glutamic acid and spermidine pretreatment in rats, which indicated the role of NMDA receptors in pioglitazone-mediated protection. It is concluded that NMDA antagonism serves as one of the mechanisms in pioglitazone-mediated protection against renal IRI in rats.

Estrogen attenuates renal IRI through PPAR-γ agonism in rats

BackgroundEstrogen is reported to be renoprotective agent in various preclinical studies, attributing to its antioxidant and anti-inflammatory potential. The aim of present study was to investigate the involvement of peroxisome proliferator-activated receptor-γ (PPAR-γ) in estrogen-mediated protection against renal ischemia reperfusion injury (IRI) in rats. Materials and methodsThe renal damage induced by IRI (40-min ischemia and 24-h reperfusion) was assessed by measuring serum creatinine, creatinine clearance, blood urea nitrogen, serum uric acid, electrolytes, and microproteinuria in rats. The myeloperoxidase activity, thiobarbituric acid reactive substances, superoxide anion generation, and reduced glutathione levels were measured to assess oxidative stress in renal tissues. Hematoxylin-eosin and periodic acid schiff staining of renal tissues were done to demonstrate histopathologic changes. Estrogen (0.2, 0.5, and 1.0 mg/kg, i.p.) was administered 1 h before subjecting rats to renal IRI. Separately, bisphenol A diglycyl ether (BADGE, 30 mg/kg, i.p.), a PPAR-γ receptor antagonist, was given before estrogen administration followed by IRI in rats. ResultsThe ischemia reperfusion demonstrated renal damage in rats with significant changes in serum and urinary parameters, enhanced oxidative stress, and histopathologic changes in renal tissues. Estrogen administration demonstrated marked renoprotection that was attenuated by BADGE pretreatment in rats. ConclusionsIt is concluded that PPAR-γ agonism serves as one of the mechanisms in estrogen-mediated renoprotection.

Mast cell stabilizers obviate high fat diet-induced renal dysfunction in rats

The present study investigated the infiltration of mast cells into the kidney tissue and the preventive role of mast cell stabilizers against high fat diet (HFD)-induced renal injury in rats. The animals were fed on HFD (30% fat) for 12 consecutive weeks to induce renal injury. The HFD-induced obesity was assessed by calculating obesity index, adiposity index, and estimation of total cholesterol, triglycerides, and high density lipoproteins in plasma. The renal dysfunction was evaluated by measuring creatinine clearance, blood urea nitrogen, uric acid, electrolytes and microproteinuria. The oxidative stress in renal tissues was determined by myeloperoxidase activity, thiobarbituric acid reactive substances, superoxide anion generation and reduced glutathione level. The systolic blood pressure (SBP) was monitored using non-invasive blood pressure measuring apparatus. Histamine and hydroxyproline contents were quantified in renal tissues. Gross histopathological changes, mast cell density and collagen deposition in the renal tissue was determined by means of histopathology. The mast cell stabilizers, sodium cromoglycate and ketotifen were administered daily for 12 weeks. The HFD fed rats demonstrated significant increase in lipid profile, kidney injury with marked increase in renal oxidative stress, SBP, mast cell density, histamine content and hydroxyproline content that was attenuated by sodium cromoglycate and ketotifen treatment. Hence, the novel findings of this investigation suggest that HFD induced mast cells infiltration into kidney tissue seems to play an important role in renal pathology, and treatment with mast cell stabilizers serves as potential therapy in management of HFD induced renal dysfunction in rats.

Dipyridamole attenuates ischemia reperfusion induced acute kidney injury through adenosinergic A1 and A2A receptor agonism in rats.

Dipyridamole (DYP) is an anti-platelet agent with marked vasodilator, anti-oxidant, and anti-inflammatory activity. The present study investigated the role of adenosine receptors in DYP-mediated protection against ischemia reperfusion-induced acute kidney injury (AKI) in rats. The rats were subjected to bilateral renal ischemia for 40min followed by reperfusion for 24h. The renal damage induced by ischemia reperfusion injury (IRI) was assessed by measuring creatinine clearance, blood urea nitrogen, uric acid, plasma potassium, fractional excretion of sodium, and microproteinuria in rats. The oxidative stress in renal tissues was assessed by quantification of thiobarbituric acid-reactive substances, superoxide anion generation, and reduced glutathione level. The hematoxylin-eosin staining was carried out to observe histopathological changes in renal tissues. DYP (10 and 30mg/kg, intraperitoneal, i.p.) was administered 30min before subjecting the rats to renal IRI. In separate groups, caffeine (50mg/kg, i.p.), an adenosinergic A1 and A2A receptor antagonist was administered with and without DYP treatment before subjecting the rats to renal IRI. The ischemia reperfusion-induced AKI was demonstrated by significant changes in serum as well as urinary parameters, enhanced oxidative stress, and histopathological changes in renal tissues. The administration of DYP demonstrated protection against AKI. The prior treatment with caffeine abolished DYP-mediated reno-protection suggesting role of A1 and A2A adenosine receptors in DYP-mediated reno-protection in rats. It is concluded that adenosine receptors find their definite involvement in DYP-mediated anti-oxidative and reno-protective effect against ischemia reperfusion-induced AKI.