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Antioxidants
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Oxidative Stress in Renal Health
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Oxidative Stress in Renal Health

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: 30 September 2024 | Viewed by 2430

Special Issue Editor

Prof. Dr. Ana Cristina Simões E Silva

E-Mail Website
Guest Editor
Departamento de Pediatria, Faculdade de Medicina UFMG, Belo Horizonte, Brazil
Interests: pediatrics; kidney function; chronic kidney disease; renin angiotensin system

Special Issue Information

Dear Colleagues,

Oxidative stress occurs due to the increase in reactive oxygen species (ROS) and reactive nitrogen species (RNS) inside the cells. ROS are capable of inducing damage to lipids, proteins, and DNA, and its increasing concentrations can also stimulate inflammation and cell death; however, low levels of ROS are necessary for cell signaling, proliferation, and growth. ROS include superoxide anions, hydrogen peroxide, and hydroxyl radicals, of which superoxide anions are significant as they are predominantly produced by nicotinamide adenine dinucleotide phosphate-oxidase (NADPH-oxidase), with NADPH-oxidase 4 (NOX4) being the most common isoform in the kidney. Therefore, precise regulation of redox homeostasis is critical for normal cellular function, particularly because changes in redox homeostasis contribute to the progression of chronic kidney disease (CKD).

Usually, inhibition of enzymatic and non-antioxidant antioxidant mechanisms leads to excessive production of ROS and RNS, causing hypertension, inflammation, fibrosis, apoptosis, and proteinuria. During inflammatory processes, ROS are produced by activated leukocytes which further increase oxidative stress. Thus, a vicious cycle is established between inflammation and oxidative stress. High levels of angiotensin II, reduced levels of nitric oxide, and hypertension also increase ROS in CKD. Hence, the recovery of redox homeostasis is being investigated as a potential therapeutic option to delay the progression of CKD.

Prof. Dr. Ana Cristina Simões E Silva
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

  • reactive oxygen species
  • reactive nitrogen species
  • oxidative stress
  • chronic kidney disease
  • redox homeostasis

Published Papers (3 papers)

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Research

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20 pages, 6613 KiB  
Article
Specific NOX4 Inhibition Preserves Mitochondrial Function and Dampens Kidney Dysfunction Following Ischemia–Reperfusion-Induced Kidney Injury
by Tomas A. Schiffer, Lucas Rannier Ribeiro Antonino Carvalho, Drielle Guimaraes, Ariela Boeder, Per Wikström and Mattias Carlström
Antioxidants 2024, 13(4), 489; https://doi.org/10.3390/antiox13040489 - 19 Apr 2024
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Abstract
Background: Acute kidney injury (AKI) is a sudden episode of kidney failure which is frequently observed at intensive care units and related to high morbidity/mortality. Although AKI can have many different causes, ischemia–reperfusion (IR) injury is the main cause of AKI. Mechanistically, [...] Read more.
Background: Acute kidney injury (AKI) is a sudden episode of kidney failure which is frequently observed at intensive care units and related to high morbidity/mortality. Although AKI can have many different causes, ischemia–reperfusion (IR) injury is the main cause of AKI. Mechanistically, NADPH oxidases (NOXs) are involved in the pathophysiology contributing to oxidative stress following IR. Previous reports have indicated that knockout of NOX4 may offer protection in cardiac and brain IR, but there is currently less knowledge about how this could be exploited therapeutically and whether this could have significant protection in IR-induced AKI. Aim: To investigate the hypothesis that a novel and specific NOX4 inhibitor (GLX7013114) may have therapeutic potential on kidney and mitochondrial function in a mouse model of IR-induced AKI. Methods: Kidneys of male C57BL/6J mice were clamped for 20 min, and the NOX4 inhibitor (GLX7013114) was administered via osmotic minipump during reperfusion. Following 3 days of reperfusion, kidney function (i.e., glomerular filtration rate, GFR) was calculated from FITC-inulin clearance and mitochondrial function was assessed by high-resolution respirometry. Renal histopathological evaluations (i.e., hematoxylin–eosin) and TUNEL staining were performed for apoptotic evaluation. Results: NOX4 inhibition during reperfusion significantly improved kidney function, as evidenced by a better-maintained GFR (p < 0.05) and lower levels of blood urea nitrogen (p < 0.05) compared to untreated IR animals. Moreover, IR caused significant tubular injuries that were attenuated by simultaneous NOX4 inhibition (p < 0.01). In addition, the level of renal apoptosis was significantly reduced in IR animals with NOX4 inhibition (p < 0.05). These favorable effects of the NOX4 inhibitor were accompanied by enhanced Nrf2 Ser40 phosphorylation and conserved mitochondrial function, as evidenced by the better-preserved activity of all mitochondrial complexes. Conclusion: Specific NOX4 inhibition, at the time of reperfusion, significantly preserves mitochondrial and kidney function. These novel findings may have clinical implications for future treatments aimed at preventing AKI and related adverse events, especially in high-risk hospitalized patients. Full article
(This article belongs to the Special Issue Oxidative Stress in Renal Health)
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25 pages, 25418 KiB  
Article
ADP-Ribosylation Factor-Interacting Protein 2 Acts as a Novel Regulator of Mitophagy and Autophagy in Podocytes in Diabetic Nephropathy
by Haihua Guo, Manuel Rogg, Julia Keller, Ann-Kathrin Scherzinger, Julia Jäckel, Charlotte Meyer, Alena Sammarco, Martin Helmstädter, Oliver Gorka, Olaf Groß, Christoph Schell and Wibke Bechtel-Walz
Antioxidants 2024, 13(1), 81; https://doi.org/10.3390/antiox13010081 - 08 Jan 2024
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Abstract
(1) Background: Differentiated podocytes are particularly vulnerable to oxidative stress and cellular waste products. The disease-related loss of postmitotic podocytes is a direct indicator of renal disease progression and aging. Podocytes use highly specific regulated networks of autophagy and endocytosis that counteract the [...] Read more.
(1) Background: Differentiated podocytes are particularly vulnerable to oxidative stress and cellular waste products. The disease-related loss of postmitotic podocytes is a direct indicator of renal disease progression and aging. Podocytes use highly specific regulated networks of autophagy and endocytosis that counteract the increasing number of damaged protein aggregates and help maintain cellular homeostasis. Here, we demonstrate that ARFIP2 is a regulator of autophagy and mitophagy in podocytes both in vitro and in vivo. (2) Methods: In a recent molecular regulatory network analysis of mouse glomeruli, we identified ADP-ribosylation factor-interacting protein 2 (Arfip2), a cytoskeletal regulator and cofactor of ATG9-mediated autophagosome formation, to be differentially expressed with age. We generated an Arfip2-deficient immortalized podocyte cell line using the CRISPR/Cas technique to investigate the significance of Arfip2 for renal homeostasis in vitro. For the in vivo analyses of Arfip2 deficiency, we used a mouse model of Streptozotozin-induced type I diabetes and investigated physiological data and (patho)histological (ultra)structural modifications. (3) Results: ARFIP2 deficiency in immortalized human podocytes impedes autophagy. Beyond this, ARFIP2 deficiency in human podocytes interferes with ATG9A trafficking and the PINK1-Parkin pathway, leading to the compromised fission of mitochondria and short-term increase in mitochondrial respiration and induction of mitophagy. In diabetic mice, Arfip2 deficiency deteriorates autophagy and leads to foot process effacement, histopathological changes, and early albuminuria. (4) Conclusions: In summary, we show that ARFIP2 is a novel regulator of autophagy and mitochondrial homeostasis in podocytes by facilitating ATG9A trafficking during PINK1/Parkin-regulated mitophagy. Full article
(This article belongs to the Special Issue Oxidative Stress in Renal Health)
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Review

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45 pages, 1651 KiB  
Review
Oxidative Stress: A Culprit in the Progression of Diabetic Kidney Disease
by Na Wang and Chun Zhang
Antioxidants 2024, 13(4), 455; https://doi.org/10.3390/antiox13040455 - 12 Apr 2024
Viewed by 467
Abstract
Diabetic kidney disease (DKD) is the principal culprit behind chronic kidney disease (CKD), ultimately developing end-stage renal disease (ESRD) and necessitating costly dialysis or kidney transplantation. The limited therapeutic efficiency among individuals with DKD is a result of our finite understanding of its [...] Read more.
Diabetic kidney disease (DKD) is the principal culprit behind chronic kidney disease (CKD), ultimately developing end-stage renal disease (ESRD) and necessitating costly dialysis or kidney transplantation. The limited therapeutic efficiency among individuals with DKD is a result of our finite understanding of its pathogenesis. DKD is the result of complex interactions between various factors. Oxidative stress is a fundamental factor that can establish a link between hyperglycemia and the vascular complications frequently encountered in diabetes, particularly DKD. It is crucial to recognize the essential and integral role of oxidative stress in the development of diabetic vascular complications, particularly DKD. Hyperglycemia is the primary culprit that can trigger an upsurge in the production of reactive oxygen species (ROS), ultimately sparking oxidative stress. The main endogenous sources of ROS include mitochondrial ROS production, NADPH oxidases (Nox), uncoupled endothelial nitric oxide synthase (eNOS), xanthine oxidase (XO), cytochrome P450 (CYP450), and lipoxygenase. Under persistent high glucose levels, immune cells, the complement system, advanced glycation end products (AGEs), protein kinase C (PKC), polyol pathway, and the hexosamine pathway are activated. Consequently, the oxidant–antioxidant balance within the body is disrupted, which triggers a series of reactions in various downstream pathways, including phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), transforming growth factor beta/p38-mitogen-activated protein kinase (TGF-β/p38-MAPK), nuclear factor kappa B (NF-κB), adenosine monophosphate-activated protein kinase (AMPK), and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling. The disease might persist even if strict glucose control is achieved, which can be attributed to epigenetic modifications. The treatment of DKD remains an unresolved issue. Therefore, reducing ROS is an intriguing therapeutic target. The clinical trials have shown that bardoxolone methyl, a nuclear factor erythroid 2-related factor 2 (Nrf2) activator, blood glucose-lowering drugs, such as sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists can effectively slow down the progression of DKD by reducing oxidative stress. Other antioxidants, including vitamins, lipoic acid, Nox inhibitors, epigenetic regulators, and complement inhibitors, present a promising therapeutic option for the treatment of DKD. In this review, we conduct a thorough assessment of both preclinical studies and current findings from clinical studies that focus on targeted interventions aimed at manipulating these pathways. We aim to provide a comprehensive overview of the current state of research in this area and identify key areas for future exploration. Full article
(This article belongs to the Special Issue Oxidative Stress in Renal Health)
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