γ-Tocotrienol Protects against Mitochondrial Dysfunction, Energy Deficits, Morphological Damage, and Decreases in Renal Functions after Renal Ischemia

Grazyna Nowak, Judit Megyesi

Int J Mol Sci . 2021 Nov 24;22(23):12674. doi: 10.3390/ijms222312674.

Abstract

Ischemia-induced mitochondrial dysfunction and ATP depletion in the kidney result in disruption of primary functions and acute injury of the kidney. This study tested whether γ-tocotrienol (GTT), a member of the vitamin E family, protects mitochondrial function, reduces ATP deficits, and improves renal functions and survival after ischemia/reperfusion injury. Vehicle or GTT (200 mg/kg) were administered to mice 12 h before bilateral kidney ischemia, and endpoints were assessed at different timepoints of reperfusion. GTT treatment reduced decreases in state 3 respiration and accelerated recovery of this function after ischemia. GTT prevented decreases in activities of complexes I and III of the respiratory chain, and blocked ischemia-induced decreases in F0F1-ATPase activity and ATP content in renal cortical tissue. GTT improved renal morphology at 72 h after ischemia, reduced numbers of necrotic proximal tubular and inflammatory cells, and enhanced tubular regeneration. GTT treatment ameliorated increases in plasma creatinine levels and accelerated recovery of creatinine levels after ischemia. Lastly, 89% of mice receiving GTT and 70% of those receiving vehicle survived ischemia. Conclusions: Our data show novel observations that GTT administration improves mitochondrial respiration, prevents ATP deficits, promotes tubular regeneration, ameliorates decreases in renal functions, and increases survival after acute kidney injury in mice.

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Protective Effect of Vitamin E on Cadmium-Induced Renal Oxidative Damage and Apoptosis in Rats

Jing Fang, Shenglan Xie, Zhuo Chen, Fengyuan Wang, Kejie Chen, Zhicai Zuo, Hengmin Cui, Hongrui Guo, Ping Ouyang, Zhengli Chen, Chao Huang, Wentao Liu, Yi Geng

Biol Trace Elem Res . 2021 Dec;199(12):4675-4687. doi: 10.1007/s12011-021-02606-4. Epub 2021 Feb 9.

Abstract

Cadmium (Cd), a widely distributed heavy metal, is extremely toxic to the kidney. Vitamin E (VE) is an important antioxidant in the body. It is known that VE exerts a protective effect on renal oxidative damage caused by Cd, but the effect and mechanism of VE on apoptosis are not fully understood. Thus, we conducted this study to explore the protective effect of VE on Cd-induced renal apoptosis and to elucidate its potential mechanism. Thirty-two 9-week-old male Sprague-Dawley rats were randomly divided into four groups, namely control, VE (100 mg/kg VE), Cd (5 mg/kg CdCl2), and VE + Cd (100 mg/kg VE + 5 mg/kg CdCl2), and received intragastric administration of Cd and/or VE for 4 weeks. The results showed that Cd exposure significantly reduced the weight of the body and kidney, elevated the accumulation of Cd in the kidney as well as the levels of BUN and Scr in serum, caused renal histological alterations, decreased the GSH and T-AOC contents and antioxidant enzyme (SOD, CAT, GSH-PX) activities, and increased renal MDA content. And the increased number of TUNEL-positive cells by Cd was accompanied by upregulated mRNA and protein expressions of apoptotic regulatory molecules (Bax, Caspase-3, GRP94, GRP78, Caspase-8) and downregulated Bcl-2 expressions. However, the combined treatment of Cd and VE could restore the above parameters to be close to those in the control rats. In conclusion, VE supplement could alleviate Cd-induced rat renal damage and oxidative stress through enhancing the antioxidant defense system and inhibiting apoptosis of renal cells.

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The effects of vitamin E on colistin-induced nephrotoxicity in treatment of drug-resistant gram-negative bacterial infections: A randomized clinical trial

Maryam Samsami, Minoosh Shabani, Mohammadreza Hajiesmaeili, Maria Tavakoli-Ardakani, Seyed Hossein Ardehali, Alireza Fatemi, Saghar Barati, Omid Moradi, Zahra Sahraei

J Infect Chemother . 2021 Aug;27(8):1181-1185. doi: 10.1016/j.jiac.2021.03.013. Epub 2021 Apr 15.

Abstract

Introduction: Nephrotoxicity remains a major long-standing concern for colistin, and it is critical to find agents that can prevent it. The present study aims to investigate the effect of vitamin E on the prevention of colistin-induced nephrotoxicity based on its antioxidant and free radical scavenging properties.

Methods: A randomized clinical trial was designed for 52 patients taking colistin. These patients were categorized into two groups of equal size, receiving colistin or colistin plus vitamin E (α-Tocopherol). Vitamin E with doses of 400 units was administrated daily either orally or by a nasogastric tube if needed. The incidence of Acute Kidney Injury (AKI) and its duration was recorded based on RIFLE criteria.

Results: The Incidence of AKI based on RIFLE criteria was 42.3% and 46.2% in intervention and control groups, respectively. The analysis showed no significant difference in the prevalence of AKI for the two groups (P = 0.78). There was no significant difference in the duration of AKI neither (P = 0.83).

Conclusion: Although vitamin E is a powerful biological antioxidant, the effects of Vitamin E prophylaxis on colistin-induced nephrotoxicity was not taken into consideration in this study.

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Implications of advanced oxidation protein products and vitamin E in atherosclerosis progression

Leila Azouaou Toualbi, Adnane Mounir, Ballouti Wafa, Arab Medina, Khelfi Abderrezak, Toualbi Chahine, Chader Henni, Bennoui Abdelghani, Seba Atmane

Arch Med Sci Atheroscler Dis . 2021 Jun 30;6:e135-e144. doi: 10.5114/amsad.2021.107823. eCollection 2021.

Abstract

Introduction: Advanced oxidation protein products (AOPP) are considered as markers of oxidative stress and inflammation, and highly predictive of atherosclerosis. Vitamin E (Vit-E) is a powerful antioxidant, but no consensus on its effectiveness at the level of AOPP or the process of atherosclerosis has been made. Hence this was the aim of the present study.

Material and methods: A longitudinal study was conducted on 205 patients with chronic kidney disease (CKD) and 40 controls. The correlations between AOPP and glomerular filtration rate (GFR) and different biological markers were analyzed. Supra-aortic trunk echo-Doppler was conducted to assess the correlation of AOPP with intima-media thickness. The effects of Vit-E treatment on AOPP levels and atherosclerosis progression were also investigated.

Results: AOPP levels increased in parallel to the alteration of renal functions in CKD patients, compared to the control group (p < 0.05). The mean value of AOPP increased concomitantly with the intima-media thickness (p < 0.05). Furthermore, AOPP mean value was higher in patients with atherosclerotic plaques (p < 0.05) compared to those without plaques. Vit-E treatment stabilized the levels of AOPP but had no effect on the atherosclerotic progression.

Conclusions: AOPP were proved to be effective markers of oxidative stress and their high levels help to predict the progression of atherosclerosis. As a powerful antioxidant, Vit-E stabilized the AOPP levels.

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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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