Kidney-Targeted Epoxyeicosatrienoic Acid Analog, EET-F01, Reduces Inflammation, Oxidative Stress, and Cisplatin-Induced Nephrotoxicity

Although epoxyeicosatrienoic acid (EET) analogs have performed well in several acute and chronic kidney disease models, targeted delivery of EET analogs to the kidney can be reasonably expected to reduce the level of drug needed to achieve a therapeutic effect and obviate possible side effects. For EET analog kidney-targeted delivery, we conjugated a stable EET analog to folic acid via a PEG-diamine linker. Next, we compared the kidney targeted EET analog, EET-F01, to a well-studied EET analog, EET-A. EET-A or EET-F01 was infused i.v. and plasma and kidney tissue collected. EET-A was detected in the plasma but was undetectable in the kidney. On the other hand, EET-F01 was detected in the plasma and kidney. Experiments were conducted to compare the efficacy of EET-F01 and EET-A for decreasing cisplatin nephrotoxicity. Cisplatin was administered to WKY rats treated with vehicle, EET-A (10 mg/kg i.p.) or EET-F01 (20 mg/kg or 2 mg/kg i.p.). Cisplatin increased kidney injury markers, viz., blood urea nitrogen (BUN), N-acetyl-β-(D)-glucosaminidase (NAG), kidney injury molecule-1 (KIM-1), and thiobarbituric acid reactive substances (TBARS). EET-F01 was as effective as EET-A in decreasing BUN, NAG, KIM-1, TBARS, and renal histological injury caused by cisplatin. Despite its almost 2×-greater molecular weight compared with EET-A, EET-F01 was comparably effective in decreasing renal injury at a 10-fold w/w lower dose. EET-F01 decreased cisplatin nephrotoxicity by reducing oxidative stress and inflammation. These data demonstrate that EET-F01 targets the kidney, allows for a lower effective dose, and combats cisplatin nephrotoxicity. In conclusion, we have developed a kidney targeted EET analog, EET-F01, that demonstrates excellent potential as a therapeutic for kidney diseases.

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Abstract 111: A Kidney Targeted Epoxyeicosatrienoic Acid Analog, EET-F01, Reduces Cisplatin-induced Nephrotoxicity

Hypertension ◽

10.1161/hyp.70.suppl_1.111 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

John D Imig ◽

Md A Khan ◽

Adeniyi M Adebesin ◽

John R Falck

Keyword(s):

Folic Acid ◽

Targeted Delivery ◽

Therapeutic Potential ◽

Kidney Diseases ◽

Kidney Tissue ◽

Renal Tissue ◽

Epoxyeicosatrienoic Acid ◽

High Concentration ◽

Lower Effective Dose

Epoxyeicosatrienoic acid (EET) analogs have exceptional therapeutic potential to combat cardiovascular and kidney diseases. EET analogs combat damage in acute and chronic kidney disease models. Biological actions attributed to EET analogs such as vasodilation, anti-inflammation, anti-apoptosis, and anti-fibrosis are ideally suited to treat kidney diseases. Although EET analogs have performed well in several in vivo models, targeted delivery of EET analogs to the kidney can be reasonably expected to reduce the level of drug needed to achieve a therapeutic effect in the kidney and obviate possible side effects. For EET analog kidney-targeted delivery, we conjugated an EET analog to folic acid because there is a high concentration of folate receptors in renal tissue. The EET analog was conjugated to folic acid via a PEG-diamine linker. Next, we compared the kidney targeted EET analog, EET-F01, to a well-studied EET analog, EET-A. EET-A or EET-F01 was infused i.v. (10mg/kg/hr) for 6 hours via the rat jugular vein. Plasma and kidney tissue were collected and EET-A or EET-F01 measured by LC-MS-MS. EET-A plasma level was 1.6 ng/mL, but EET-A was undetectable in the kidney. On the other hand, EET-F01 was 6.5 ng/mL in plasma and 26.7 ng/mL in kidney tissue. These data demonstrate that EET-F01 targets the kidney. Experiments were conducted to compare EET-F01 and EET-A to decrease cisplatin-induced nephrotoxicity. A single injection of cisplatin (7 mg/kg ip) was administered to WKY rats treated with vehicle, EET-A (10 mg/kg ip) or EET-F01 (20 mg/kg or 2 mg/kg ip) for five days. Cisplatin increased BUN (125 ± 11 mg/dL) and NAG (12 ± 4 IU/L) compared to control (36 ± 9 mg/dL and 4 ± 1 IU/L). EET-F01 was as effective as EET-A in decreasing BUN, NAG, and renal histological injury five days following cisplatin administration. Despite it almost 2x-greater molecular weight compared with EET-A, EET-F01 was effective in lowering BUN and NAG at 20 mg/kg/d and at a 10-fold lower dose of 2 mg/kg/d. These data clearly demonstrate that EET-F01 targets the kidney and allows for a lower effective dose. In conclusion, we have developed a kidney targeted EET analog, EET-F01, that demonstrates excellent potential as a therapeutic for kidney diseases.

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A H2S Donor GYY4137 Exacerbates Cisplatin-Induced Nephrotoxicity in Mice

Mediators of Inflammation ◽

10.1155/2016/8145785 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 15

Author(s):

Mi Liu ◽

Zhanjun Jia ◽

Ying Sun ◽

Aihua Zhang ◽

Tianxin Yang

Keyword(s):

Oxidative Stress ◽

Renal Dysfunction ◽

Kidney Diseases ◽

Kidney Injury ◽

Apoptotic Response ◽

Cisplatin Nephrotoxicity ◽

Histological Damage ◽

Structural Injury ◽

Elevated Blood Urea Nitrogen

Accumulating evidence demonstrated that hydrogen sulfide (H2S) is highly involved in inflammation, oxidative stress, and apoptosis and contributes to the pathogenesis of kidney diseases. However, the role of H2S in cisplatin nephrotoxicity is still debatable. Here we investigated the effect of GYY4137, a novel slow-releasing H2S donor, on cisplatin nephrotoxicity in mice. Male C57BL/6 mice were pretreated with GYY4137 for 72 h prior to cisplatin injection. After cisplatin treatment for 72 h, mice developed obvious renal dysfunction and kidney injury as evidenced by elevated blood urea nitrogen (BUN) and histological damage. Consistently, these mice also showed increased proinflammatory cytokines such as TNF-α, IL-6, and IL-1βin circulation and/or kidney tissues. Meanwhile, circulating thiobarbituric aid-reactive substances (TBARS) and renal apoptotic indices including caspase-3, Bak, and Bax were all elevated. However, application of GYY4137 further aggravated renal dysfunction and kidney structural injury in line with promoted inflammation, oxidative stress, and apoptotic response following cisplatin treatment. Taken together, our results suggested that GYY4137 exacerbated cisplatin-induced nephrotoxicity in mice possibly through promoting inflammation, oxidative stress, and apoptotic response.

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Metabolic Disorders in Nigerians Occupationally Exposed to Cement Dust

European Scientific Journal ESJ ◽

10.19044/esj.2016.v12n33p57 ◽

2016 ◽

Vol 12 (33) ◽

pp. 57

Author(s):

Moses Akiibinu ◽

Mary Adeyemi ◽

Toyosi Ogunbiyi ◽

Mojirade Amusah ◽

Adeolu Amusan ◽

...

Keyword(s):

Oxidative Stress ◽

Macrophage Activation ◽

Metabolic Disorders ◽

Kidney Diseases ◽

Kidney Injury ◽

Stress Index ◽

Cement Dust ◽

Exposed Workers ◽

Occupationally Exposed ◽

Kidney Injury Molecule 1

Exposures to cement dust have been linked with lung dysfunctions in some occupationally exposed workers. There is a dearth of information on the potentials of the cement particles to induce tumorigenesis, kidney failure and oxidative stress in the exposed workers. This study assessed the effects of cement exposure on macrophage activation, tumor markers, kidney injury molecule-1 and markers of oxidative stress in cement loaders with prolonged exposures. Twenty-nine male workers who had direct exposure to cement dust and gases for a period of 2-30 years in Elephant / Lafarge cement depot Ibadan, Nigeria, were recruited for this study. Another twenty apparently healthy individuals who had no interaction with cement served as controls. Levels of carcino-embryonic antigen (CEA), alpha fetoprotein (AFP), kidney injury molecule-1 (KIM-1), DNA-8-hydroxyguanosine (8-OHdG), neopterin, total plasma peroxide (TPP), total antioxidant potential (TAP), oxidative stress index (OSI), malondialdehyde (MDA) and albumin were determined in all participants using ELISA and spectrophotometry methods respectively. The result shows significantly (p0.05) changes observed in the plasma levels of albumin and AFP when compared with the controls. No significant (p>0.05) correlations could be observed between the levels of 8-OHdG, neopterin, albumin, MDA, CEA, AFP, KIM-1 and OSI in the cement exposed workers. Metabolic disorders including excessive macrophage activation, oxidative DNA damage, kidney diseases and chemically-induced tumors are imminent in cement exposed workers.

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Combination therapy of cisplatin with cilastatin enables an increased dose of cisplatin, enhancing its antitumor effect by suppression of nephrotoxicity

Scientific Reports ◽

10.1038/s41598-020-80853-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Masashi Arita ◽

Satoshi Watanabe ◽

Nobumasa Aoki ◽

Shoji Kuwahara ◽

Ryo Suzuki ◽

...

Keyword(s):

Anticancer Agents ◽

Cell Injury ◽

Kidney Injury ◽

Antitumor Effects ◽

Cisplatin Nephrotoxicity ◽

Proximal Tubular ◽

Nephrotoxic Drugs ◽

Kidney Injury Molecule 1 ◽

Dose Dependent

AbstractCisplatin, one of the most active anticancer agents, is widely used in standard chemotherapy for various cancers. Cisplatin is more poorly tolerated than other chemotherapeutic drugs, and the main dose-limiting toxicity of cisplatin is its nephrotoxicity, which is dose-dependent. Although less toxic methods of cisplatin administration have been established, cisplatin-induced nephrotoxicity remains an unsolved problem. Megalin is an endocytic receptor expressed at the apical membrane of proximal tubules. We previously demonstrated that nephrotoxic drugs, including cisplatin, are reabsorbed through megalin and cause proximal tubular cell injury. We further found that cilastatin blocked the binding of cisplatin to megalin in vitro. In this study, we investigated whether cilastatin could reduce cisplatin-induced nephrotoxicity without influencing the antitumor effects of cisplatin. Nephrotoxicity was decreased or absent in mice treated with cisplatin and cilastatin, as determined by kidney injury molecule-1 staining and the blood urea nitrogen content. Combined with cilastatin, a twofold dose of cisplatin was used to successfully treat the mice, which enhanced the antitumor effects of cisplatin but reduced its nephrotoxicity. These findings suggest that we can increase the dose of cisplatin when combined with cilastatin and improve the outcome of cancer patients.

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Antioxidant Activity, Phenolic Profile, and Nephroprotective Potential of Anastatica hierochuntica Ethanolic and Aqueous Extracts against CCl4-Induced Nephrotoxicity in Rats

Nutrients ◽

10.3390/nu13092973 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2973

Author(s):

Tariq I. Almundarij ◽

Yousef M. Alharbi ◽

Hassan A. Abdel-Rahman ◽

Hassan Barakat

Keyword(s):

Oxidative Stress ◽

Antioxidant Activity ◽

Therapeutic Agent ◽

Kidney Tissue ◽

Kidney Injury ◽

Total Phenolic ◽

Drug Induced ◽

Total Carotenoids ◽

Phenolic Profile ◽

Better Than

Kaff-e-Maryam (Anastatica hierochuntica L.) is extensively used to treat a range of health problems, most notably to ease childbirth and alleviate reproductive system-related disorders. This study aimed to evaluate the effect of A. hierochuntica ethanolic (KEE), and aqueous (KAE) extracts on CCl4-induced oxidative stress and nephrotoxicity in rats using the biochemical markers for renal functions and antioxidant status as well as histopathological examinations of kidney tissue. A. hierochuntica contained 67.49 mg GAE g−1 of total phenolic compounds (TPC), 3.51 µg g−1 of total carotenoids (TC), and 49.78 and 17.45 mg QE g−1 of total flavonoids (TF) and total flavonols (TFL), respectively. It resulted in 128.71 µmol of TE g−1 of DPPH-RSA and 141.92 µmol of TE g−1 of ABTS-RSA. A. hierochuntica presented superior antioxidant activity by inhibiting linoleic acid radicals and chelating oxidation metals. The HPLC analysis resulted in 9 and 21 phenolic acids and 6 and 2 flavonoids in KEE and KAE with a predominance of sinapic and syringic acids, respectively. Intramuscular injection of vit. E + Se and oral administration of KEE, KAE, and KEE + KAE at 250 mg kg−1 body weight significantly restored serum creatinine, urea, K, total protein, and albumin levels. Additionally, they reduced malondialdehyde (MOD), restored reduced-glutathione (GSH), and enhanced superoxide dismutase (SOD) levels. KEE, KAE, and KEE + KAE protected the kidneys from CCl4-nephrotoxicity as they mainly attenuated induced oxidative stress. Total nephroprotection was about 83.27%, 97.62%, and 78.85% for KEE, KAE, and KEE + KAE, respectively. Both vit. E + Se and A. hierochuntica extracts attenuated the histopathological alteration in CCl4-treated rats. In conclusion, A. hierochuntica, especially KAE, has the potential capability to restore oxidative stability and improve kidney function after CCl4 acute kidney injury better than KEE. Therefore, A. hierochuntica has the potential to be a useful therapeutic agent in the treatment of drug-induced nephrotoxicity.

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Reduced O-GlcNAcylation and tubular hypoxia contribute to the antifibrotic effect of SGLT2 inhibitor dapagliflozin in the diabetic kidney

AJP Renal Physiology ◽

10.1152/ajprenal.00021.2020 ◽

2020 ◽

Vol 318 (4) ◽

pp. F1017-F1029 ◽

Cited By ~ 5

Author(s):

Judit Hodrea ◽

Dora B. Balogh ◽

Adam Hosszu ◽

Lilla Lenart ◽

Balazs Besztercei ◽

...

Keyword(s):

High Glucose ◽

Kidney Diseases ◽

Combined Treatment ◽

Hypoxia Inducible Factor ◽

Sglt2 Inhibitor ◽

Kidney Injury ◽

Diabetic Kidney ◽

Neutrophil Gelatinase Associated Lipocalin ◽

Male Wistar Rats ◽

Kidney Injury Molecule 1

Diabetic kidney disease is a worldwide epidemic, and therapies are incomplete. Clinical data suggest that improved renal outcomes by Na+-glucose cotransporter 2 inhibitor (SGLT2i) are partly beyond their antihyperglycemic effects; however, the mechanisms are still elusive. Here, we investigated the effect of the SGLT2i dapagliflozin (DAPA) in the prevention of elevated O-GlcNAcylation and tubular hypoxia as contributors of renal fibrosis. Type 1 diabetes was induced by streptozotocin in adult male Wistar rats. After the onset of diabetes, rats were treated for 6 wk with DAPA or DAPA combined with losartan (LOS). The effect of hyperglycemia was tested in HK-2 cells kept under normal or high glucose conditions. To test the effect of hypoxia, cells were kept in 1% O2 for 2 h. Cells were treated with DAPA or DAPA combined with LOS. DAPA slowed the loss of renal function, mitigated renal tubular injury markers (kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin), and reduced tubulointerstitial fibrosis. DAPA diminished high glucose-induced protein O-GlcNAcylation and moderated the tubular response to hypoxia through the hypoxia-inducible factor pathway. DAPA alone was as effective as combined treatment with LOS in all outcome parameters. These data highlight the role of ameliorated O-GlcNAcylation and diminished tubular hypoxia as important benefits of SGLT2i treatment. Our results support the link between glucose toxicity, tubular hypoxia, and fibrosis, a vicious trio that could be targeted by SGLT2i in kidney diseases of other origins as well.

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Tissue Kidney Injury Molecule-1 Expression in the Prediction of Renal Function for Several Years after Kidney Biopsy

Disease Markers ◽

10.1155/2013/183246 ◽

2013 ◽

Vol 35 ◽

pp. 567-572 ◽

Cited By ~ 5

Author(s):

Sanja Simic Ogrizovic ◽

Suzana Bojic ◽

Gordana Basta-Jovanovic ◽

Sanja Radojevic ◽

Jelena Pavlovic ◽

...

Keyword(s):

Renal Function ◽

Retrospective Study ◽

Kidney Function ◽

Kidney Biopsy ◽

Kidney Diseases ◽

Kidney Injury ◽

Mdrd Formula ◽

Positive Correlations ◽

Kidney Injury Molecule 1 ◽

Kidney Functions

Objectives. Retrospective study was designed to examine the importance of tissue kidney injury molecule-1 (KIM-1) expression in predicting kidney function in sixty patients (27 males) aged 34.15 ± 12.23 years with different kidney diseases over three years after kidney biopsy.Materials and Methods. Tissue KIM-1 expression was determined immunohistochemically and KIM-1 staining was scored semiquantitatively, as well as tubulointerstitialis (TIN), inflammation, atrophy, and fibrosis. Kidney function (MDRD formula) and proteinuria/day were evaluated at the time of biopsy (GFR0) and 6, 12, 24, and 36 months later.Results. Significantly positive correlations between tissue KIM-1 expression and age (r=0.313), TIN inflammation (r=0.456), fibrosis (r=0.317), and proteinuria at 6 months (r=0.394) as well as negative correlations with GFR0 (r=−0.572), GFR6 (r=−0.442), GFR24 (r=−0.398), and GFR36 (r=−0.412) were found. Meanwhile, TIN inflammation was the best predictor of all measured kidney functions during three years, while tissue KIM-1 expression (P=0.016) was a predictor only at 6 months after biopsy.Conclusion. Tissue KIM-1 expression significantly predicts kidney function solely at 6 months after biopsy, when the effects of immune and nonimmune treatments are the strongest.

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Screening of early diagnostic markers of gentamicin-induced acute kidney injury in canines

Journal of Veterinary Research ◽

10.2478/jvetres-2019-0048 ◽

2019 ◽

Vol 63 (3) ◽

pp. 405-411

Author(s):

Jia-San Zheng ◽

Jing-Nie ◽

Ting-Ting Zhu ◽

Hong-Ri Ruan ◽

Xue-Wei ◽

...

Keyword(s):

Acute Kidney Injury ◽

Characteristic Curve ◽

Kidney Tissue ◽

Kidney Injury ◽

Fatty Acid Binding ◽

Neutrophil Gelatinase Associated Lipocalin ◽

Transmission Electron ◽

Renal Tubular ◽

Kidney Injury Molecule 1 ◽

Neutrophil Gelatinase

Abstract Introduction The value of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (Kim-1), and liver-type fatty acid binding protein (L-FABP) was assessed in early diagnosis of gentamicin-induced acute kidney injury (AKI) in dogs. Material and Methods Subcutaneous gentamicin injection in 16 healthy adult beagles made the AKI model. Blood was sampled every 6 h to detect NGAL, Kim-1, L-FABP, and serum creatinine (SCr) concentrations. Kidney tissue of two dogs was taken before the injection, as soon as SCr was elevated (78 μmol/L), and when it had risen to 1.5 times the baseline, and haematoxylin-eosin staining and transmission electron microscopy (TEM) were used to observe changes. Results NGAL, Kim-1, and SCr levels were significantly increased (P < 0.05) at 18, 30, and 78 h post injection, but L-FABP concentration was not associated with renal injury. At the earliest SCr elevation stage, findings were mild oedema, degeneration, and vacuolisation in renal tubular epithelial cells in pathology, and mild cytoplasmic and mitochondrial oedema in TEM. At this time point, NGAL and Kim-1 concentrations were significantly increased (P < 0.05), indicating that these two molecules biomark early kidney injury in dogs. Using receiver operating characteristic curve analysis, their warning levels were > 25.31 ng/mL and > 48.52 pg/mL. Conclusion Plasma NGAL and Kim-1 above warning levels are early indicators of gentamicin-induced AKI in dogs.

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The Inhibitory Impact of Schisandrin Against LPS-Induced Acute Kidney Injury in Vitro and in Vivo

10.21203/rs.3.rs-935326/v1 ◽

2021 ◽

Author(s):

Weifeng Li ◽

Qiuxia Huang ◽

Jinjin Yu ◽

Jiabao Yu ◽

Yajie Yang ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Kidney Tissue ◽

Kidney Injury ◽

Immunohistochemical Analysis ◽

Inflammatory Factors ◽

Raw264.7 Macrophages ◽

Bioactive Component

Abstract Schisandrin (Sch) is a main bioactive component of Schisandra sphenanthera Rehd.et Wils. It has been reported that Sch could regulate inflammatory disease. This study evaluated the anti-inflammatory and anti-oxidant effects effect of Sch on lipopolysaccharide (LPS)-induced macrophages activation and acute kidney injury mice. Male Kunming mice were intraperitoneally injected with LPS (15 mg/kg) after administration of Sch (12.5, 25, 50 mg/kg) seven days for developing acute kidney injury vivo model. RAW264.7 macrophages were pretreatment Sch (10, 20, 40 µM) and administrated LPS (1 µg/ml) to create an in vitro injury model. ELISA results found that Sch administration reduced the production of inflammatory factors induced by LPS in kidney tissues and RAW264.7 macrophages. It has been observed that Sch alleviated oxidative stress by reducing the levels of reactive oxygen species, myeloperoxidase and malondialdehyde, and increasing the activity of superoxide dismutase and glutathione peroxidase. Hematoxylin-eosin staining data suggested that Sch administration significantly reduced inflammatory cell infiltration and the kidney tissue damage induced by LPS. The blood urea nitrogen and creatinine levels were also reduced by Sch treatment. In addition, Western blot and immunohistochemical analysis showed that Sch up-regulated the expression of Nrf2 and HO-1, and decreased the expression of p-p38, p-JNK, p-ERK1/2, p-IκBα, p-NF-κBp65 and TLR4. The current research showed that Sch reduced LPS-induced acute kidney injury by inhibiting inflammation and oxidative stress, and provided insights into potential ways to treat AKI.

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The Effect of Superoxide Dismutase on Inhibition of Acute Kidney Injury Induced by Sepsis Based on Kidney Tissue Histology and Murine Sepsis Score

The Scientific World JOURNAL ◽

10.1155/2021/1827296 ◽

2021 ◽

Vol 2021 ◽

pp. 1-7

Author(s):

Jufitriani Ismy ◽

Maimun Syukri ◽

Dessy R. Emril ◽

Nanan Sekarwana ◽

Jufriady Ismy ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Superoxide Dismutase ◽

Kidney Tissue ◽

Kidney Injury ◽

Male Rats ◽

Control Group ◽

Control Group Design ◽

Group I ◽

Sepsis Score

Sepsis is one of the leading causes contributing to the incidence of acute kidney injury (AKI). Oxidative stress can be used as the main approach against sepsis-induced AKI. One of the primary antioxidants that plays a role in warding off oxidative stress is superoxide dismutase (SOD). This research aimed to observe the effect of antioxidant SOD in inhibiting sepsis in AKI based on kidney tissue histopathology. The research method was an experimental laboratory with a post-test-only control group design. Twenty-five adult male rats aged 12–16 weeks, weighing between 200 and 250 g, were randomly divided into five groups: Group I, as a positive control, where rats were injected with lipopolysaccharides (LPS); Group II, as a negative control; Group III, as treatment 1, where rats were injected with LPS and administered orally with SOD (Glisodin®) 250 IU daily; Group IV, as treatment 2, where rats were injected with LPS and administered orally with SOD (Glisodin®) 500 IU daily; and Group V, as treatment 2, where rats were injected with LPS and administered orally with SOD (Glisodin®) 1000 IU daily. Rats were administered with SOD (Glisodin®) by oral gavage with a flexible feeding tube for 16 weeks, given once daily in the morning, and then injected with LPS of 10 mg/kg body weight. Glisodin SOD had a significant effect on murine sepsis score (MSS). MSS influenced the tubular injury score linearly. We conclude that the optimal dose of SOD at 1000 IU for inhibiting sepsis-induced AKI incidence is compared to SOD at a dose of 250 and 500 IU. The antioxidant effect of SOD can prevent sepsis-induced AKI with oxidative stress events.

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