Inhibition of endoplasmic reticulum stress and activation of autophagy-protect intestinal and renal tissues from western diet-induced dysbiosis and abrogate inflammatory response to LPS: role of vitamin E

A M Shamseldeen, M Hamzawy, N A Mahmoud, L Rashed, S S Kamar, L A Harb, N Sharawy

J Biol Regul Homeost Agents . Mar-Apr 2021;35(2):457-471. doi: 10.23812/20-693-A.

Abstract

Diet pattern is an emerging risk factor for renal disease. The mechanism by which high-fat high fructose (western) diet mediates renal injury is not yet fully understood. The objective of the present study was to investigate the relationship between endoplasmic reticulum (ER) stress and autophagy in the development of renal impairment and aggravation of the inflammatory response. Eighty male rats were randomly divided into four groups as follows: a standard diet-fed (ConD), a high-fat high fructose diet fed (HFHF-V), ConD fed and orally supplemented with vitamin E (ConD-E), and HFHF fed and orally supplemented vitamin E (HFHF-E). After 12 weeks, either lipopolysaccharide (LPS) or saline was injected. We found that upregulation of endoplasmic reticulum stress-related proteins rendered the cells susceptible to injury induced by dysbiosis and microbiota-derived metabolites. A downregulation of autophagy and upregulation of caspase-12 resulted in the loss of intestinal integrity and renal tubular injury. Maintained ER stress also increased the inflammatory response to LPS. In contrast, vitamin E effectively ameliorated ER stress and promoted autophagy to protect intestinal and renal tissues. Our results provide insight into the influences of sustained ER stress activation and autophagy inhibition on the development of renal injury, which may contribute also to the enhanced inflammatory response.

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The effects of vitamin E supplementation on malondialdehyde as a biomarker of oxidative stress in haemodialysis patients: a systematic review and meta-analysis

Peter Bergin, Aoife Leggett, Chris R Cardwell, Jayne V Woodside, Ammarin Thakkinstian, Alexander P Maxwell, Gareth J McKay

BMC Nephrol . 2021 Apr 9;22(1):126. doi: 10.1186/s12882-021-02328-8.

Abstract

Background: Haemodialysis (HD) patients tend to have higher levels of oxidative stress (OS), associated with increased morbidity and premature mortality, compared to the general population. Levels of malondialdehyde (MDA), a biomarker of OS, are reduced by the antioxidant properties of vitamin E (VE) but outcomes from randomised control trials of VE supplementation on MDA in HD patients have been inconsistent.

Methods: We undertook a systematic review and meta-analysis of adult HD patients from VE supplementation studies with measures of MDA. The following search criteria of MEDLINE and EMBASE were considered from inception to January 2020: ‘dialysis’ AND ‘Vitamin E OR tocopherol’ AND ‘malondialdehyde OR MDA’. Two reviewers independently extracted study data and assessed risk of bias. Mean MDA levels and standard deviation were determined before and after VE supplementation. Standardised mean difference (SMD) and standard error were calculated as the within person difference and units of measure were not consistently recorded across all studies. The SMD were pooled using random effects meta-analysis.

Results: The SMD of MDA levels from 18 comparisons was significantly lower in HD patients following VE supplementation (- 1.55; confidence interval: – 2.17 to – 0.94, P < 0.00001). There were significant levels of heterogeneity between studies (I2 value = 91%; P < 0.00001) with evidence of potential publication bias toward smaller studies.

Conclusions: Our findings support the use of VE to reduce the effects of OS in HD patients although high levels of heterogeneity and variation in the methodological approaches used by some studies highlight the need for further investigation.

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A Phase IIb Randomized Controlled Trial Investigating the Effects of Tocotrienol-Rich Vitamin E on Diabetic Kidney Disease

Yan Yi Koay, Gerald Chen Jie Tan, Sonia Chew Wen Phang, J-Ian Ho, Pei Fen Chuar, Loon Shin Ho, Badariah Ahmad, Khalid Abdul Kadir

Nutrients . 2021 Jan 18;13(1):258. doi: 10.3390/nu13010258.

Abstract

Diabetic kidney disease (DKD) is a debilitating complication of diabetes, which develops in 40% of the diabetic population and is responsible for up to 50% of end-stage renal disease (ESRD). Tocotrienols have shown to be a potent antioxidant, anti-inflammatory, and antifibrotic agent in animal and clinical studies. This study evaluated the effects of 400 mg tocotrienol-rich vitamin E supplementation daily on 59 DKD patients over a 12-month period. Patients with stage 3 chronic kidney disease (CKD) or positive urine microalbuminuria (urine to albumin creatinine ratio; UACR > 20-200 mg/mmol) were recruited into a randomized, double-blind, placebo-controlled trial. Patients were randomized into either intervention group (n = 31) which received tocotrienol-rich vitamin E (Tocovid SupraBioTM; Hovid Berhad, Ipoh, Malaysia) 400 mg daily or a placebo group which received placebo capsules (n = 28) for 12 months. HbA1c, renal parameters (i.e., serum creatinine, eGFR, and UACR), and serum biomarkers were collected at intervals of two months. Tocovid supplementation significantly reduced serum creatinine levels (MD: -4.28 ± 14.92 vs. 9.18 ± 24.96), p = 0.029, and significantly improved eGFR (MD: 1.90 ± 5.76 vs. -3.29 ± 9.24), p = 0.011 after eight months. Subgroup analysis of 37 patients with stage 3 CKD demonstrated persistent renoprotective effects over 12 months; Tocovid improved eGFR (MD: 4.83 ± 6.78 vs. -1.45 ± 9.18), p = 0.022 and serum creatinine (MD: -7.85(20.75) vs. 0.84(26.03), p = 0.042) but not UACR. After six months post washout, there was no improvement in serum creatinine and eGFR. There were no significant changes in the serum biomarkers, TGF-β1 and VEGF-A. Our findings verified the results from the pilot phase study where tocotrienol-rich vitamin E supplementation at two and three months improved kidney function as assessed by serum creatinine and eGFR but not UACR.

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Comparing the renoprotective effects of the antioxidants melatonin, vitamin D and vitamin E in diabetic rats

Abdulmonim A Alqasim, Essam Eldin M Nour Eldin, Sami H Hammadi, Ghada E Esheba

J Taibah Univ Med Sci . 2020 Jul 17;15(5):351-357. doi: 10.1016/j.jtumed.2020.05.007. eCollection 2020 Oct.

Abstract

Objectives: Diabetes mellitus is associated with oxidative stress that leads to inflammation and diabetic nephropathy. This study aimed to determine the possible renoprotective effects of the antioxidants melatonin, vitamin D and vitamin E in diabetic rats.

Methods: We divided 108 albino rats into 12 groups. G1 group was fed a normal diet and did not receive any medication. G2 to G4 consisted of non-diabetic rats that were treated as follows: G2 with melatonin; G3 with vitamin E; G4 with vitamin D. Groups G5 to G12 consisted of diabetic rats that were treated as follows: G5 received no medication; G6 treated with insulin; G7 treated with melatonin; G8 treated with melatonin and insulin; G9 treated with vitamin E; G10 treated with vitamin E and insulin; G11 treated with vitamin D and G12 treated with vitamin D and insulin. Two months after treatment commenced, histological and biochemical examinations of glucose profile, oxidative stress status, renal function, homocysteine and TNF-α were performed.

Results: Total antioxidant capacity (TAC) increased significantly in groups G2, 7, 8, 10 and 11. TNF-α significantly increased in G2, but decreased in all other groups. Creatinine increased significantly in groups G5, 6, 7, 8, 9, 11 and 12. In the kidneys of the diabetic rats, thickened capillary basement membrane, diffuse mesangial sclerosis and nodular glomerulosclerosis was observed. Rats treated with melatonin showed marked improvement in these symptoms. However, in those treated with vitamin D and E, thickened capillary basement membrane and mesangial sclerosis was still present.

Conclusions: Melatonin, administered either with or without insulin had a significant biochemical antioxidant effect and histological renoprotective effect. Conversely, vitamin D and E did not appear to have any effects on the parameters measured.

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The protective efficacy of vitamin E and cod liver oil against cisplatin-induced acute kidney injury in rats

Azza M A Abo-Elmaaty, Amany Behairy, Nesma I El-Naseery, Mohamed M Abdel-Daim

Environ Sci Pollut Res Int . 2020 Aug 7. doi: 10.1007/s11356-020-10351-9. Online ahead of print.

Abstract

Cisplatin (CP) is a highly effective chemotherapeutic agent against neoplasms, but its clinical utility is limited due to the side effects of its dose-dependent nephrotoxicity. Vitamin E (Vit E) and cod liver oil (CLO) are natural substances with chemoprotective effects. The present study was conducted to evaluate the protective effects of Vit E and/or CLO for CP-induced acute kidney injury (AKI) in rats. This study involved 40 mature male Wistar albino rats that were equally allocated into eight groups: Veh, Vit E, CLO, Vit E + CLO, CP, Vit E + CP, CLO + CP, and Vit E + CLO + CP. The co-administration of Vit E and CLO significantly ameliorated CP-induced elevations in serum creatinine (Cr), blood urea nitrogen (BUN), interleukin 1 beta (IL-1β), and interleukin- 6 (IL-6). Further, rats that received Vit E and/or CLO showed significant decrease in malondialdehyde (MDA) and increases in superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels in renal tissues, compared to CP-intoxicated rats. Additionally, the treatment restored the normal histological architecture (except for few cast formations) and upregulated the immunostaining area% of aquaporin 3 (AQP3) and downregulated the immunostaining area% of Bcl2 associated X protein (BAX) and inducible nitric oxide synthase (iNOS). The observed effects were stronger in the combination treatment group. The obtained data revealed that Vit E and CLO co-administration protects against the CP-induced AKI more than monotherapy with Vit E or CLO.

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Cardiac and Renal Protective Effect of Vitamin E in Dexamethasone-Induced Oxidative Stressed Wistar Rats

Daniel U Owu, Idara A Okon, Usenobong F Ufot, Justin A Beshel

Niger J Physiol Sci . 2020 Jun 30;35(1):52-60.

Abstract

Vitamin E has been used as antioxidant and in the treatment of various ailments due to oxidative stress. The cardio-protective effect of vitamin E in dexamethasone induced oxidative stress was studied. Forty Wistar rats were randomly assigned to four groups of 10 rats each. Control group received normal rat chow. Oxidative stress was induced using 30µg/kg body weight of dexamethasone (DEX) intraperitonealy in DEX+Vit E and DEX only groups while Vitamin E was administered orally at a dose of 300 IU/kg to Vitamin E only group and DEX+Vit E group daily for 14 days. All animals were fed ad libitum and had free access to water. Blood samples were obtained by cardiac puncture for biochemical analyses while heart and kidney were processed for histological staining. The result shows a significant (p<0.05) decrease in serum nitric oxide, bilirubin and superoxide dismutase concentration in DEX-only group which was elevated following vitamin E treatment. The angiotensin converting enzyme and lactate dehydrogenase enzyme activities were significantly (p<0.01) elevated in DEX-only group compared with control and DEX+Vit E groups. These enzyme levels were significantly (p<0.01) reduced in DEX + vitamin E group. The histology of the heart and the kidney in DEX-only group showed cardiac hypertrophy and kidney injury but were ameliorated by vitamin E treatment. The results suggest that vitamin E has cardiac and renal protective effect and ameliorates oxidative injury to the heart and kidney due to oxidative stress.

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Effects of Vitamin A and Vitamin E on Attenuation of Amphotericin B-induced Side Effects on Kidney and Liver of Male Wistar Rats

Aref Salehzadeh, Alireza Salehzadeh, Amir-Hossein Maghsood, Shirin Heidarisasan, Masoumeh Taheri-Azandaryan, Abolfazl Ghafourikhosroshahi, Roghayeh Abbasalipourkabir

Environ Sci Pollut Res Int . 2020 Jun 8. doi: 10.1007/s11356-020-09547-w. Online ahead of print.

Abstract

Despite the fact that amphotericin B (AmB) is currently considered as the first choice for treatment of visceral leishmaniasis, it is associated with some side effects. This study was designed to investigate the protective effects of vitamins A and E against amphotericin B-induced adverse effects in the kidney and liver of rat. Thirty male Wistar rats aged 7-8 weeks and weighing around 200 g were randomly divided into five groups, each one containing six rats. The first to fifth groups received olive oil as the control groups, AmB, AmB + vitamin A, AmB + vitamin E, and AmB + vitamins A + E, respectively. Rats received vitamins by gavage (vitamin A, 1000 IU/kg and vitamin E, 100 IU/kg) and amphotericin B by injections (5.5 mg/kg body weight). The treatment was constantly continued for 5 days and days 7 and 21. At the end of the study, serum level of TAC, TOS, MDA, liver enzyme activity (ALT, AST, ALP, LDH), renal factors (urea, uric acid, and creatinine), lipid profile as well as histopathological changes of the liver and kidney were investigated. AmB significantly increased serum level of creatinine, urea, uric acid, ALP, TOS, MDA, and kidney and renal tissue damage (p < 0.05). Supplementation AmB with vitamins A and E alone or combination improved oxidative stress status, liver and renal tissue structure, and functional parameters and serum lipid profile. This study highlighted the effects of vitamin A and vitamin E on attenuation of amphotericin B-induced side effects on the kidney and liver of male Wistar rats. Combination of the two vitamins is more effective than either alone improving the oxidative stress status, serum lipid profile, or liver and renal tissue structure and functional parameters.

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Vitamin E-Bonded Membranes Do Not Influence Markers of Oxidative Stress in Hemodialysis Patients With Homozygous Glutathione Transferase M1 Gene Deletion

Petar Djuric, Sonja Suvakov, Tatjana Simic, Dragana Markovic, Djurdja Jerotic, Aleksandar Jankovic 1, Ana Bulatovic, Jelena Tosic Dragovic, Tatjana Damjanovic, Jelena Marinkovic, Radomir Naumovic, Nada Dimkovic

Toxins (Basel) . 2020 May 27;12(6):E352. doi: 10.3390/toxins12060352.

Abstract

Background: Increased oxidative stress is a hallmark of end-stage renal disease. Hemodialysis (HD) patients lacking glutathione transferase M1 (GSTM1) enzyme activity exhibit enhanced oxidative DNA damage and higher mortality rate than those with active GSTM1 enzyme. To our knowledge, this is the first study to use the vitamin E-bonded membranes (VEM) in patients with homozygous GSTM1 gene deletion, and we aimed to determine the effect of VEM on oxidative and inflammatory status in HD patients with homozygous GSTM1 gene deletion.

Methods: GSTM1 genotypes were determined by polymerase chain reaction (PCR) in 170 chronic HD patients. Those with GSTM1-null genotype were randomized and 80 were included in the study. Forty of them were dialyzed for three months with VEM, while the other forty were dialyzed with high-flux same-surface polysulfone dialyzers. Markers of protein and lipid oxidative damage and inflammation (thiol groups, malondialdehyde (MDA), Interleukin-6 (IL-6)), together with plasma antioxidant activity (glutathione peroxidase (GPX), superoxide dismutase (SOD)) were determined.

Results: Seventy-five patients finished the study. There were no differences at baseline in markers of protein and lipid oxidative damage, inflammation and plasma antioxidant activity. After three months of therapy, GPX, MDA, and thiol groups increased significantly in both groups, but without statistical significance between groups. SOD and C reactive protein (CRP) did not change significantly during the three-month period. IL-6 increased in the control group, and at the same time, decreased in the VEM group, but without statistical significance. Hemoglobin (Hb) value, red blood cells, erythropoiesis resistance index (ERI), serum ferritin and iron did not change significantly within or between groups. Regarding other laboratory parameters, proteins, albumins, triglycerides, serum phosphorus, serum bicarbonate and Kt/V showed significant improvements within groups but with no significant difference between groups.

Conclusions: Our data shows that therapy with VEM over three months had no benefit over standard polysulfone membrane in decreasing by-products of oxidative stress and inflammation in dialysis patients lacking GSTM1 enzyme activity.

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