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Antioxidants
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Oxidative Stress in Kidney Disease
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Oxidative Stress in Kidney Disease

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 58402

Special Issue Editor

Dr. Munehiro Kitada

E-Mail Website
Guest Editor
Department of Diabetology and Endocrinology, Kanazawa Medical University, Ishikawa, Japan
Interests: Mitochondrial oxidative stress; diabetic kidney disease; autophagy; low-protein diet

Special Issue Information

Dear Colleagues,

Chronic kidney disease (CKD) is one of the fastest-growing causes of death worldwide, emphasizing the need to develop novel therapeutic approaches. Additionally, CKD predisposes to acute kidney injury (AKI), and AKI favors CKD progression. Dysregulation of redox homeostasis by imbalance between reactive oxygen species (ROS) production and defense systems against ROS under pathological conditions results in oxidative stress. Oxidative stress promotes the progression of renal diseases, including CKD and AKI, and it is a common pathophysiological feature of both AKI and CKD. Therefore, oxidative stress-targeting therapies are expected as nephroprotective agents.    
        This Special Issue entitled “Oxidative Stress and Kidney Disease” welcomes the submission of either original research manuscripts or reviews of the scientific literature concerning the mechanism of ROS overproduction, alteration of the defense system against ROS, antioxidants, and various renal outcomes. In addition, the role of phytochemicals, nutraceuticals, and dietary patterns in the control of redox-dependent pathophysiological conditions on kidney disease will be considered. I sincerely hope that this Special Issue will advance our understanding of how oxidative stress contribute to kidney disease.

Dr. Munehiro Kitada
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Oxidative stress
  • Chronic kidney disease
  • Acute kidney injury

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Published Papers (17 papers)

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Research

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17 pages, 4427 KiB  
Article
Immunohistochemical Analysis of 4-HNE, NGAL, and HO-1 Tissue Expression after Apocynin Treatment and HBO Preconditioning in Postischemic Acute Kidney Injury Induced in Spontaneously Hypertensive Rats
by Sanjin Kovacevic, Milan Ivanov, Maja Zivotic, Predrag Brkic, Zoran Miloradovic, Rada Jeremic, Nevena Mihailovic-Stanojevic, Una Jovana Vajic, Danijela Karanovic, Djurdjica Jovovic and Jelena Nesovic Ostojic
Antioxidants 2021, 10(8), 1163; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10081163 - 22 Jul 2021
Cited by 9 | Viewed by 2866
Abstract
Oxidative stress has been considered as a central aggravating factor in the development of postischemic acute kidney injury (AKI). The aim of this study was to perform the immunohistochemical analysis of 4-hydroxynonenal (4-HNE), neutrophil gelatinase-associated lipocalin (NGAL), and heme oxygenase-1 (HO-1) tissue expression [...] Read more.
Oxidative stress has been considered as a central aggravating factor in the development of postischemic acute kidney injury (AKI). The aim of this study was to perform the immunohistochemical analysis of 4-hydroxynonenal (4-HNE), neutrophil gelatinase-associated lipocalin (NGAL), and heme oxygenase-1 (HO-1) tissue expression after apocynin (APO) treatment and hyperbaric oxygenation (HBO) preconditioning, applied as single or combined protocol, in postischemic acute kidney injury induced in spontaneously hypertensive rats (SHR). Twenty-four hours before AKI induction, HBO preconditioning was carried out by exposing to pure oxygen (2.026 bar) twice a day, for 60 min in two consecutive days. Acute kidney injury was induced by removal of the right kidney while the left renal artery was occluded for 45 min by atraumatic clamp. Apocynin was applied in a dose of 40 mg/kg body weight, intravenously, 5 min before reperfusion. We showed increased 4-HNE renal expression in postischemic AKI compared to Sham-operated (SHAM) group. Apocynin treatment, with or without HBO preconditioning, improved creatinine and phosphate clearances, in postischemic AKI. This improvement in renal function was accompanied with decreased 4-HNE, while HO-1 kidney expression restored close to the control group level. NGAL renal expression was also decreased after apocynin treatment, and HBO preconditioning, with or without APO treatment. Considering our results, we can say that 4-HNE tissue expression can be used as a marker of oxidative stress in postischemic AKI. On the other hand, apocynin treatment and HBO preconditioning reduced oxidative damage, and this protective effect might be expected even in experimental hypertensive condition. Full article
(This article belongs to the Special Issue Oxidative Stress in Kidney Disease)
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12 pages, 1314 KiB  
Article
Nox4 Maintains Blood Pressure during Low Sodium Diet
by Flávia Rezende, Pedro Felipe Malacarne, Niklas Müller, Birgit Rathkolb, Martin Hrabě de Angelis, Katrin Schröder and Ralf P Brandes
Antioxidants 2021, 10(7), 1103; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10071103 - 10 Jul 2021
Cited by 2 | Viewed by 2034
Abstract
The NADPH oxidase Nox4 is a hydrogen peroxide (H2O2)-producing enzyme, with the highest expression in the kidney. As the kidney is involved in volume and blood pressure control through sodium handling, we set out to determine the impact of [...] Read more.
The NADPH oxidase Nox4 is a hydrogen peroxide (H2O2)-producing enzyme, with the highest expression in the kidney. As the kidney is involved in volume and blood pressure control through sodium handling, we set out to determine the impact of a low sodium diet on these parameters in WT and Nox4-/- mice. Nox4 expression in the murine kidney was restricted to the proximal tubule. Nevertheless, low-sodium-induced weight loss and sodium sparing function was similar in WT and Nox4-/- mice, disputing an important function of renal Nox4 in sodium handling. In contrast, a low sodium diet resulted in a reduction in systolic blood pressure in Nox4-/- as compared to WT mice. This was associated with a selectively lower pressure to heart-rate ratio, as well as heart to body weight ratio. In general, a low sodium diet leads to activation of sympathetic tone and the renin angiotensin system, which subsequently increases peripheral resistance. Our observations suggest that the control by this system is attenuated in Nox4-/- mice, resulting in lower blood pressure in response to low sodium. Full article
(This article belongs to the Special Issue Oxidative Stress in Kidney Disease)
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17 pages, 1219 KiB  
Article
Urinary Carnosinase-1 Excretion is Associated with Urinary Carnosine Depletion and Risk of Graft Failure in Kidney Transplant Recipients: Results of the TransplantLines Cohort Study
by Angelica Rodriguez-Niño, Diego O. Pastene, Adrian Post, M. Yusof Said, Antonio W. Gomes-Neto, Lyanne M. Kieneker, M. Rebecca Heiner-Fokkema, Tuba Esatbeyoglu, Gerald Rimbach, Peter Schnuelle, Benito A. Yard and Stephan J. L. Bakker
Antioxidants 2021, 10(7), 1102; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10071102 - 09 Jul 2021
Cited by 2 | Viewed by 1711
Abstract
Carnosine affords protection against oxidative and carbonyl stress, yet high concentrations of the carnosinase-1 enzyme may limit this. We recently reported that high urinary carnosinase-1 is associated with kidney function decline and albuminuria in patients with chronic kidney disease. We prospectively investigated whether [...] Read more.
Carnosine affords protection against oxidative and carbonyl stress, yet high concentrations of the carnosinase-1 enzyme may limit this. We recently reported that high urinary carnosinase-1 is associated with kidney function decline and albuminuria in patients with chronic kidney disease. We prospectively investigated whether urinary carnosinase-1 is associated with a high risk for development of late graft failure in kidney transplant recipients (KTRs). Carnosine and carnosinase-1 were measured in 24 h urine in a longitudinal cohort of 703 stable KTRs and 257 healthy controls. Cox regression was used to analyze the prospective data. Urinary carnosine excretions were significantly decreased in KTRs (26.5 [IQR 21.4–33.3] µmol/24 h versus 34.8 [IQR 25.6–46.8] µmol/24 h; p < 0.001). In KTRs, high urinary carnosinase-1 concentrations were associated with increased risk of undetectable urinary carnosine (OR 1.24, 95%CI [1.06–1.45]; p = 0.007). During median follow-up for 5.3 [4.5–6.0] years, 84 (12%) KTRs developed graft failure. In Cox regression analyses, high urinary carnosinase-1 excretions were associated with increased risk of graft failure (HR 1.73, 95%CI [1.44–2.08]; p < 0.001) independent of potential confounders. Since urinary carnosine is depleted and urinary carnosinase-1 imparts a higher risk for graft failure in KTRs, future studies determining the potential of carnosine supplementation in these patients are warranted. Full article
(This article belongs to the Special Issue Oxidative Stress in Kidney Disease)
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13 pages, 3662 KiB  
Article
Urinary Spermidine Predicts and Associates with In-Hospital Acute Kidney Injury after Cardiac Surgery
by Marta Martin-Lorenzo, Angeles Ramos-Barron, Paula Gutierrez-Garcia, Ariadna Martin-Blazquez, Aranzazu Santiago-Hernandez, Emilio Rodrigo Calabia, Carlos Gomez-Alamillo and Gloria Alvarez-Llamas
Antioxidants 2021, 10(6), 896; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10060896 - 02 Jun 2021
Cited by 5 | Viewed by 2365
Abstract
Acute Kidney Injury (AKI) affects up to 30% of the patients who undergo cardiac surgery (CVS) and is related to higher mortality. We aim to investigate molecular features associated with in-hospital AKI development and determine the predictive value of these features when analyzed [...] Read more.
Acute Kidney Injury (AKI) affects up to 30% of the patients who undergo cardiac surgery (CVS) and is related to higher mortality. We aim to investigate molecular features associated with in-hospital AKI development and determine the predictive value of these features when analyzed preoperatively. This is a case-control study. From an initial cohort of 110 recruited subjects, a total of 60 patients undergoing cardiac surgery were included: 20 (33%) developed in-hospital AKI (CVS-AKI) and 40 did not (controls, CVS-C). Pre- and post-surgery samples were collected and a prospective study was carried out. A total of 312 serum samples and 258 urine samples were analyzed by nuclear magnetic resonance, mass spectrometry and ELISA. Six features predicted AKI development in pre-surgery samples: urinary kidney functional loss marker kidney injury molecule-1 (uKIM-1), 2-hydroxybutyric acid, 2-hydroxyphenylacetic acid, hippuric acid, phosphoethanolamine and spermidine. Two of them stood out as powerful predictors. Pre-surgery uKIM-1 levels were increased in CVS-AKI vs. CVS-C (AUC = 0.721, p-value = 0.0392) and associated strongly with the outcome (OR = 5.333, p-value = 0.0264). Spermidine showed higher concentration in CVS-AKI (p-value < 0.0001, AUC = 0.970) and had a strong association with the outcome (OR = 69.75, p-value < 0.0001). uKIM-1 and particularly spermidine predict in-hospital AKI associated with CVS in preoperative samples. These findings may aid in preventing postoperative AKI and improve prognosis of CVS. Full article
(This article belongs to the Special Issue Oxidative Stress in Kidney Disease)
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18 pages, 5192 KiB  
Article
Caffeic Acid Phenethyl Ester Protects Kidney Mitochondria against Ischemia/Reperfusion Induced Injury in an In Vivo Rat Model
by Justina Kamarauskaite, Rasa Baniene, Darius Trumbeckas, Arvydas Strazdauskas and Sonata Trumbeckaite
Antioxidants 2021, 10(5), 747; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10050747 - 08 May 2021
Cited by 11 | Viewed by 3540
Abstract
To improve ischemia/reperfusion tolerance, a lot of attention has been focused on natural antioxidants. Caffeic acid phenethyl ester (CAPE), an active component of the resinous exudates of the buds and young leaves of Populus nigra L., Baccharis sarothroides A., etc., and of propolis, [...] Read more.
To improve ischemia/reperfusion tolerance, a lot of attention has been focused on natural antioxidants. Caffeic acid phenethyl ester (CAPE), an active component of the resinous exudates of the buds and young leaves of Populus nigra L., Baccharis sarothroides A., etc., and of propolis, possesses unique biological activities such as anti-inflammatory, antioxidant, immunomodulating, and cardioprotective effects, among others. There is a lack of studies showing a link between the antioxidant potential of CAPE and the mechanism of protective action of CAPE at the level of mitochondria, which produces the main energy for the basic functions of the cell. In the kidney, ischemia/reperfusion injury contributes to rapid kidney dysfunction and high mortality rates, and the search for biologically active protective compounds remains very actual. Therefore, the aim of this study was to identify the antioxidant potential of CAPE and to investigate whether CAPE can protect rat kidney mitochondria from in vivo kidney ischemia/reperfusion induced injury. We found that CAPE (1) possesses antioxidant activity (the reducing properties of CAPE are more pronounced than its antiradical properties); CAPE effectively reduces cytochrome c; (2) protects glutamate/malate oxidation and Complex I activity; (3) preserves the mitochondrial outer membrane from damage and from the release of cytochrome c; (4) inhibits reactive oxygen species (ROS) generation in the Complex II (SDH) F site; (5) diminishes ischemia/reperfusion-induced LDH release and protects from necrotic cell death; and (6) has no protective effects on succinate oxidation and on Complex II +III activity, but partially protects Complex II (SDH) from ischemia/reperfusion-induced damage. In summary, our study shows that caffeic acid phenethyl ester protects kidney mitochondrial oxidative phosphorylation and decreases ROS generation at Complex II in an in vivo ischemia/reperfusion model, and shows potential as a therapeutic agent for the development of pharmaceutical preparations against oxidative stress-related diseases. Full article
(This article belongs to the Special Issue Oxidative Stress in Kidney Disease)
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10 pages, 953 KiB  
Article
Urolithiasis Develops Endothelial Dysfunction as a Clinical Feature
by Javier Sáenz-Medina, María Martinez, Silvia Rosado, Manuel Durán, Dolores Prieto and Joaquín Carballido
Antioxidants 2021, 10(5), 722; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10050722 - 04 May 2021
Cited by 5 | Viewed by 2226
Abstract
An increased risk of cardiovascular morbidity has been reported in lithiasic patients. In this context, endothelial dysfunction (ED), an earlier status of atherogenesis, has been identified in hyperoxaluria rat models of urolithiasis. Objective: The purpose of this study was to determine the endothelial [...] Read more.
An increased risk of cardiovascular morbidity has been reported in lithiasic patients. In this context, endothelial dysfunction (ED), an earlier status of atherogenesis, has been identified in hyperoxaluria rat models of urolithiasis. Objective: The purpose of this study was to determine the endothelial vascular function in patients with urolithiasis in relation to systemic inflammatory, oxidative stress, and vascular function serum markers. Methods: A cross-sectional study was performed between 27 urolithiasic patients, matched for age and sex, with 27 healthy patients. Endothelial function was assessed by measuring flow-mediated dilation (Celermajer method). Fasting blood was collected to determine metabolic parameters (glucose and lipid profile), along with serum CRP, IL-6, MDA, ADMA, and VCAM-1. Results: Both the control and urolithiasis groups were homogenous in anthropometric, exploration, and general laboratory measures. Flow-mediated dilation (%FMD) was 11.85% (SE: 2.78) lower in the lithiasis group (p < 0.001). No significant differences were achieved between groups when CRP, IL-6, MDA, ADMA, and VCAM-1 were compared, although slightly higher values of CRP, ADMA, and VCAM-1 were detected in the lithiasic group. A correlation was not reached in any of the serum markers when they were related to flow-mediated values, although a slight negative correlation trend was observed in MDA, VCAM-1, and IL-6 values. Conclusions: Endothelial dysfunction constitutes an important disorder related to urolithiasis patients. It must be considered as an early feature responsible for future cardiovascular events. Our study did not find a significant association between inflammatory, oxidative stress, endothelial serum markers, and flow-mediated dilation. Full article
(This article belongs to the Special Issue Oxidative Stress in Kidney Disease)
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16 pages, 3170 KiB  
Article
Inhibition of p300 by Garcinol Protects against Cisplatin-Induced Acute Kidney Injury through Suppression of Oxidative Stress, Inflammation, and Tubular Cell Death in Mice
by Jung-Yeon Kim, Jungmin Jo, Jaechan Leem and Kwan-Kyu Park
Antioxidants 2020, 9(12), 1271; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9121271 - 14 Dec 2020
Cited by 28 | Viewed by 2674
Abstract
Emerging evidence suggests that epigenetic mechanisms such as histone modification are crucially involved in the pathophysiology of acute kidney injury (AKI). The histone acetyltransferase p300 regulates several biological processes through the acetylation of histones or transcription factors. However, the role of p300 in [...] Read more.
Emerging evidence suggests that epigenetic mechanisms such as histone modification are crucially involved in the pathophysiology of acute kidney injury (AKI). The histone acetyltransferase p300 regulates several biological processes through the acetylation of histones or transcription factors. However, the role of p300 in cisplatin-induced AKI remains poorly understood. Therefore, we investigated the effects of garcinol, a potent p300 inhibitor, on cisplatin-induced AKI and explored the mechanisms. Administration of garcinol significantly reversed the upregulation of p300 and increased acetylation of histone H3, along with amelioration of renal dysfunction and histopathological injury in the kidneys of cisplatin-injected mice. Garcinol also attenuated oxidative stress and reduced expression of pro-oxidant enzymes. In addition, garcinol reduced the elevated production of cytokines and chemokines and suppressed immune cell accumulation together with downregulation of vascular adhesion molecules. These beneficial effects of garcinol were associated with a reduction in acetylation of the p65 subunit of nuclear factor kappa-B. Further, garcinol significantly inhibited apoptosis and caspase-3 activation, with a decrease in p53 acetylation in cisplatin-injected mice. Taken together, we demonstrated that the inhibition of p300 by garcinol ameliorated cisplatin-induced renal injury, presumably through epigenetic mechanisms. These results suggest that garcinol might be a potential preventive agent for cisplatin-induced AKI. Full article
(This article belongs to the Special Issue Oxidative Stress in Kidney Disease)
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25 pages, 5262 KiB  
Article
Nephroprotective Effect of Cilastatin against Gentamicin-Induced Renal Injury In Vitro and In Vivo without Altering Its Bactericidal Efficiency
by Juan Carlos Jado, Blanca Humanes, María Ángeles González-Nicolás, Sonia Camaño, José Manuel Lara, Beatriz López, Emilia Cercenado, Julio García-Bordas, Alberto Tejedor and Alberto Lázaro
Antioxidants 2020, 9(9), 821; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9090821 - 03 Sep 2020
Cited by 21 | Viewed by 4095
Abstract
Gentamicin is a used antibiotic that causes nephrotoxicity in 10–20% of treatment periods, which limits its use considerably. Our results have shown that cilastatin may be a promising therapeutic alternative in toxin-induced acute kidney injury (AKI). Here, we investigated its potential use as [...] Read more.
Gentamicin is a used antibiotic that causes nephrotoxicity in 10–20% of treatment periods, which limits its use considerably. Our results have shown that cilastatin may be a promising therapeutic alternative in toxin-induced acute kidney injury (AKI). Here, we investigated its potential use as a nephroprotector against gentamicin-induced AKI in vitro and in vivo. Porcine renal cells and rats were treated with gentamicin and/or cilastatin. In vivo nephrotoxicity was analyzed by measuring biochemical markers and renal morphology. Different apoptotic, oxidative and inflammatory parameters were studied at cellular and systemic levels. Megalin, mainly responsible for the entry of gentamicin into the cells, was also analyzed. Results show that cilastatin protects cells from gentamicin-induced AKI. Cilastatin decreased creatinine, BUN, kidney injury molecule-1 (KIM-1) and severe morphological changes previously increased by gentamicin in rats. The interference of cilastatin with lipid rafts cycling leads to decreased expression of megalin, and therefore gentamicin uptake and myeloid bodies, resulting in a decrease of apoptotic, oxidative and inflammatory events. Moreover, cilastatin did not prevent bacterial death by gentamicin. Cilastatin reduced gentamicin-induced AKI by preventing key steps in the amplification of the damage, which is associated to the disruption of megalin-gentamicin endocytosis. Therefore, cilastatin might represent a novel therapeutic tool in the prevention and treatment of gentamicin-induced AKI in the clinical setting. Full article
(This article belongs to the Special Issue Oxidative Stress in Kidney Disease)
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20 pages, 16366 KiB  
Article
Hippuric Acid Promotes Renal Fibrosis by Disrupting Redox Homeostasis via Facilitation of NRF2–KEAP1–CUL3 Interactions in Chronic Kidney Disease
by Bowen Sun, Xifan Wang, Xiaoxue Liu, Longjiao Wang, Fazheng Ren, Xiaoyu Wang and Xiaojing Leng
Antioxidants 2020, 9(9), 783; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9090783 - 25 Aug 2020
Cited by 34 | Viewed by 4498
Abstract
Chronic kidney disease (CKD) is characterized by the accumulation of protein-bound uremic toxins (PBUTs), which play a pathophysiological role in renal fibrosis (a common pathological process resulting in CKD progression). Accumulation of the PBUT hippuric acid (HA) is positively correlated with disease progression [...] Read more.
Chronic kidney disease (CKD) is characterized by the accumulation of protein-bound uremic toxins (PBUTs), which play a pathophysiological role in renal fibrosis (a common pathological process resulting in CKD progression). Accumulation of the PBUT hippuric acid (HA) is positively correlated with disease progression in CKD patients, suggesting that HA may promote renal fibrosis. Oxidative stress is the most important factor affecting PBUTs nephrotoxicity. Herein, we assessed the ability of HA to promote kidney fibrosis by disrupting redox homeostasis. In HK-2 cells, HA increased fibrosis-related gene expression, extracellular matrix imbalance, and oxidative stress. Additionally, reactive oxygen species (ROS)-mediated TGFβ/SMAD signaling contributed to HA-induced fibrotic responses. HA disrupted antioxidant networks by decreasing the levels of nuclear factor erythroid 2-related factor 2 (NRF2), leading to ROS accumulation and fibrotic responses, as evidenced by NRF2 activation and knockdown. Moreover, NRF2 levels were reduced by NRF2 ubiquitination, which was regulated via increased interactions of Kelch-like ECH-associated protein 1 with Cullin 3 and NRF2. Finally, renal fibrosis and redox imbalance promoted by HA were confirmed in rats. Importantly, sulforaphane (NRF2 activator) reversed HA-promoted renal fibrosis. Thus, HA promotes renal fibrosis in CKD by disrupting NRF2-driven antioxidant system, indicating that NRF2 is a potential therapeutic target for CKD. Full article
(This article belongs to the Special Issue Oxidative Stress in Kidney Disease)
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Review

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19 pages, 1582 KiB  
Review
Kidney Protection with the Radical Scavenger α1-Microglobulin (A1M) during Peptide Receptor Radionuclide and Radioligand Therapy
by Amanda Kristiansson, Anders Örbom, Oskar Vilhelmsson Timmermand, Jonas Ahlstedt, Sven-Erik Strand and Bo Åkerström
Antioxidants 2021, 10(8), 1271; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10081271 - 10 Aug 2021
Cited by 6 | Viewed by 3393
Abstract
α1-Microglobulin (A1M) is an antioxidant found in all vertebrates, including humans. It has enzymatic reductase activity and can scavenge radicals and bind free heme groups. Infused recombinant A1M accumulates in the kidneys and has therefore been successful in protecting kidney injuries [...] Read more.
α1-Microglobulin (A1M) is an antioxidant found in all vertebrates, including humans. It has enzymatic reductase activity and can scavenge radicals and bind free heme groups. Infused recombinant A1M accumulates in the kidneys and has therefore been successful in protecting kidney injuries in different animal models. In this review, we focus on A1M as a radioprotector of the kidneys during peptide receptor radionuclide/radioligand therapy (PRRT/RLT). Patients with, e.g., neuroendocrine tumors or castration resistant prostate cancer can be treated by administration of radiolabeled small molecules which target and therefore enable the irradiation and killing of cancer cells through specific receptor interaction. The treatment is not curative, and kidney toxicity has been reported as a side effect since the small, radiolabeled substances are retained and excreted through the kidneys. In recent studies, A1M was shown to have radioprotective effects on cell cultures as well as having a similar biodistribution as the somatostatin analogue peptide 177Lu-DOTATATE after intravenous infusion in mice. Therefore, several animal studies were conducted to investigate the in vivo radioprotective potential of A1M towards kidneys. The results of these studies demonstrated that A1M co-infusion yielded protection against kidney toxicity and improved overall survival in mouse models. Moreover, two different mouse studies reported that A1M did not interfere with tumor treatment itself. Here, we give an overview of radionuclide therapy, the A1M physiology and the results from the radioprotector studies of the protein. Full article
(This article belongs to the Special Issue Oxidative Stress in Kidney Disease)
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30 pages, 1406 KiB  
Review
Sirtuins and Renal Oxidative Stress
by Yoshio Ogura, Munehiro Kitada and Daisuke Koya
Antioxidants 2021, 10(8), 1198; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10081198 - 27 Jul 2021
Cited by 33 | Viewed by 5137
Abstract
Renal failure is a major health problem that is increasing worldwide. To improve clinical outcomes, we need to understand the basic mechanisms of kidney disease. Aging is a risk factor for the development and progression of kidney disease. Cells develop an imbalance of [...] Read more.
Renal failure is a major health problem that is increasing worldwide. To improve clinical outcomes, we need to understand the basic mechanisms of kidney disease. Aging is a risk factor for the development and progression of kidney disease. Cells develop an imbalance of oxidants and antioxidants as they age, resulting in oxidative stress and the development of kidney damage. Calorie restriction (CR) is recognized as a dietary approach that promotes longevity, reduces oxidative stress, and delays the onset of age-related diseases. Sirtuins, a type of nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase, are considered to be anti-aging molecules, and CR induces their expression. The sirtuin family consists of seven enzymes (Sirt1–7) that are involved in processes and functions related to antioxidant and oxidative stress, such as DNA damage repair and metabolism through histone and protein deacetylation. In fact, a role for sirtuins in the regulation of antioxidants and redox substances has been suggested. Therefore, the activation of sirtuins in the kidney may represent a novel therapeutic strategy to enhancing resistance to many causative factors in kidney disease through the reduction of oxidative stress. In this review, we discuss the relationship between sirtuins and oxidative stress in renal disease. Full article
(This article belongs to the Special Issue Oxidative Stress in Kidney Disease)
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17 pages, 1243 KiB  
Review
Metabolic Changes and Oxidative Stress in Diabetic Kidney Disease
by Midori Sakashita, Tetsuhiro Tanaka and Reiko Inagi
Antioxidants 2021, 10(7), 1143; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10071143 - 19 Jul 2021
Cited by 30 | Viewed by 3747
Abstract
Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease, and it is crucial to understand the pathophysiology of DKD. The control of blood glucose levels by various glucose-lowering drugs, the common use of inhibitors of the renin–angiotensin system, and the [...] Read more.
Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease, and it is crucial to understand the pathophysiology of DKD. The control of blood glucose levels by various glucose-lowering drugs, the common use of inhibitors of the renin–angiotensin system, and the aging of patients with diabetes can alter the disease course of DKD. Moreover, metabolic changes and associated atherosclerosis play a major role in the etiology of DKD. The pathophysiology of DKD is largely attributed to the disruption of various cellular stress responses due to metabolic changes, especially an increase in oxidative stress. Therefore, many antioxidants have been studied as therapeutic agents. Recently, it has been found that NRF2, a master regulator of oxidative stress, plays a major role in the pathogenesis of DKD and bardoxolone methyl, an activator of NRF2, has attracted attention as a drug that increases the estimated glomerular filtration rate in patients with DKD. This review outlines the altered stress responses of cellular organelles in DKD, their involvement in the pathogenesis of DKD, and discusses strategies for developing therapeutic agents, especially bardoxolone methyl. Full article
(This article belongs to the Special Issue Oxidative Stress in Kidney Disease)
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13 pages, 1080 KiB  
Review
The Pivotal Role of Oxidative Stress in the Pathophysiology of Cardiovascular-Renal Remodeling in Kidney Disease
by Verdiana Ravarotto, Giovanni Bertoldi, Georgie Innico, Laura Gobbi and Lorenzo A. Calò
Antioxidants 2021, 10(7), 1041; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10071041 - 29 Jun 2021
Cited by 16 | Viewed by 3353
Abstract
The excessive activation of the renin-angiotensin system in kidney disease leads to alteration of intracellular pathways which concur altogether to the induction of cardiovascular and renal remodeling, exposing these patients since the very beginning of the renal injury to chronic kidney disease and [...] Read more.
The excessive activation of the renin-angiotensin system in kidney disease leads to alteration of intracellular pathways which concur altogether to the induction of cardiovascular and renal remodeling, exposing these patients since the very beginning of the renal injury to chronic kidney disease and progression to end stage renal disease, a very harmful and life threatening clinical condition. Oxidative stress plays a pivotal role in the pathophysiology of renal injury and cardiovascular-renal remodeling, the long-term consequence of its effect. This review will examine the role of oxidative stress in the most significant pathways involved in cardiovascular and renal remodeling with a focus on the detrimental effects of oxidative stress-mediated renal abnormalities on the progression of the disease and of its complications. Food for thoughts on possible therapeutic target are proposed on the basis of experimental evidences. Full article
(This article belongs to the Special Issue Oxidative Stress in Kidney Disease)
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20 pages, 1968 KiB  
Review
Indoxyl-Sulfate-Induced Redox Imbalance in Chronic Kidney Disease
by Chien-Lin Lu, Cai-Mei Zheng, Kuo-Cheng Lu, Min-Tser Liao, Kun-Lin Wu and Ming-Chieh Ma
Antioxidants 2021, 10(6), 936; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10060936 - 09 Jun 2021
Cited by 25 | Viewed by 4483
Abstract
The accumulation of the uremic toxin indoxyl sulfate (IS) induces target organ damage in chronic kidney disease (CKD) patients, and causes complications including cardiovascular diseases, renal osteodystrophy, muscle wasting, and anemia. IS stimulates reactive oxygen species (ROS) production in CKD, which impairs glomerular [...] Read more.
The accumulation of the uremic toxin indoxyl sulfate (IS) induces target organ damage in chronic kidney disease (CKD) patients, and causes complications including cardiovascular diseases, renal osteodystrophy, muscle wasting, and anemia. IS stimulates reactive oxygen species (ROS) production in CKD, which impairs glomerular filtration by a direct cytotoxic effect on the mesangial cells. IS further reduces antioxidant capacity in renal proximal tubular cells and contributes to tubulointerstitial injury. IS-induced ROS formation triggers the switching of vascular smooth muscular cells to the osteoblastic phenotype, which induces cardiovascular risk. Low-turnover bone disease seen in early CKD relies on the inhibitory effects of IS on osteoblast viability and differentiation, and osteoblastic signaling via the parathyroid hormone. Excessive ROS and inflammatory cytokine releases caused by IS directly inhibit myocyte growth in muscle wasting via myokines’ effects. Moreover, IS triggers eryptosis via ROS-mediated oxidative stress, and elevates hepcidin levels in order to prevent iron flux in circulation in renal anemia. Thus, IS-induced oxidative stress underlies the mechanisms in CKD-related complications. This review summarizes the underlying mechanisms of how IS mediates oxidative stress in the pathogenesis of CKD’s complications. Furthermore, we also discuss the potential role of oral AST-120 in attenuating IS-mediated oxidative stress after gastrointestinal adsorption of the IS precursor indole. Full article
(This article belongs to the Special Issue Oxidative Stress in Kidney Disease)
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17 pages, 245 KiB  
Review
Excessively Enlarged Mitochondria in the Kidneys of Diabetic Nephropathy
by Kiyoung Kim and Eun-Young Lee
Antioxidants 2021, 10(5), 741; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10050741 - 07 May 2021
Cited by 12 | Viewed by 2738
Abstract
Diabetic nephropathy (DN) is the most serious complication of diabetes and a leading cause of kidney failure and mortality in patients with diabetes. However, the exact pathogenic mechanisms involved are poorly understood. Impaired mitochondrial function and accumulation of damaged mitochondria due to increased [...] Read more.
Diabetic nephropathy (DN) is the most serious complication of diabetes and a leading cause of kidney failure and mortality in patients with diabetes. However, the exact pathogenic mechanisms involved are poorly understood. Impaired mitochondrial function and accumulation of damaged mitochondria due to increased imbalance in mitochondrial dynamics are known to be involved in the development and progression of DN. Accumulating evidence suggests that aberrant mitochondrial fission is involved in the progression of DN. Conversely, studies linking excessively enlarged mitochondria to DN pathogenesis are emerging. In this review, we summarize the current concepts of imbalanced mitochondrial dynamics and their molecular aspects in various experimental models of DN. We discuss the recent evidence of enlarged mitochondria in the kidneys of DN and examine the possibility of a therapeutic application targeting mitochondrial dynamics in DN. Full article
(This article belongs to the Special Issue Oxidative Stress in Kidney Disease)
18 pages, 1389 KiB  
Review
Developmental Origins of Kidney Disease: Why Oxidative Stress Matters?
by Chien-Ning Hsu and You-Lin Tain
Antioxidants 2021, 10(1), 33; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10010033 - 30 Dec 2020
Cited by 36 | Viewed by 4640
Abstract
The “developmental origins of health and disease” theory indicates that many adult-onset diseases can originate in the earliest stages of life. The developing kidney has emerged as being particularly vulnerable to adverse in utero conditions leading to morphological and functional changes, namely renal [...] Read more.
The “developmental origins of health and disease” theory indicates that many adult-onset diseases can originate in the earliest stages of life. The developing kidney has emerged as being particularly vulnerable to adverse in utero conditions leading to morphological and functional changes, namely renal programming. Emerging evidence indicates oxidative stress, an imbalance between reactive oxygen/nitrogen species (ROS/RNS) and antioxidant systems, plays a pathogenetic role in the developmental programming of kidney disease. Conversely, perinatal use of antioxidants has been implemented to reverse programming processes and prevent adult-onset diseases. We have termed this reprogramming. The focus of this review is twofold: (1) To summarize the current knowledge on oxidative stress implicated in renal programming and kidney disease of developmental origins; and (2) to provide an overview of reprogramming effects of perinatal antioxidant therapy on renal programming and how this may prevent adult-onset kidney disease. Although early-life oxidative stress is implicated in mediating renal programming and adverse offspring renal outcomes, and animal models provide promising results to allow perinatal antioxidants applied as potential reprogramming interventions, it is still awaiting clinical translation. This presents exciting new challenges and areas for future research. Full article
(This article belongs to the Special Issue Oxidative Stress in Kidney Disease)
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9 pages, 950 KiB  
Perspective
Roles of mTOR in Diabetic Kidney Disease
by Mako Yasuda-Yamahara, Shinji Kume and Hiroshi Maegawa
Antioxidants 2021, 10(2), 321; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10020321 - 22 Feb 2021
Cited by 27 | Viewed by 2864
Abstract
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease and the number of patients affected is increasing worldwide. Thus, there is a need to establish a new treatment for DKD to improve the renal prognosis of diabetic patients. Recently, it [...] Read more.
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease and the number of patients affected is increasing worldwide. Thus, there is a need to establish a new treatment for DKD to improve the renal prognosis of diabetic patients. Recently, it has shown that intracellular metabolic abnormalities are involved in the pathogenesis of DKD. In particular, the activity of mechanistic target of rapamycin complex 1 (mTORC1), a nutrient-sensing signaling molecule, is hyperactivated in various organs of diabetic patients, which suggests the involvement of excessive mTORC1 activation in the pathogenesis of diabetes. In DKD, hyperactivated mTORC1 may be involved in the pathogenesis of podocyte damage, which causes proteinuria, and tubular cell injury that decreases renal function. Therefore, elucidating the role of mTORC1 in DKD and developing new therapeutic agents that suppress mTORC1 hyperactivity may shed new light on DKD treatments in the future. Full article
(This article belongs to the Special Issue Oxidative Stress in Kidney Disease)
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