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Oxidative Stress in Renal Health

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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 (30 September 2024) | Viewed by 16864

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Prof. Dr. Ana Cristina Simões E Silva

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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

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Keywords

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

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Published Papers (9 papers)

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Research

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16 pages, 4022 KiB

Open AccessArticle

Berberine Mitigates Sepsis-Associated Acute Kidney Injury in Aged Rats by Preserving Mitochondrial Integrity and Inhibiting TLR4/NF-κB and NLRP3 Inflammasome Activations

by Ruedeemars Yubolphan, Anongporn Kobroob, Apisek Kongkaew, Natthakarn Chiranthanut, Natthanicha Jinadang and Orawan Wongmekiat

Antioxidants 2024, 13(11), 1398; https://doi.org/10.3390/antiox13111398 - 15 Nov 2024

Viewed by 356

Abstract

Sepsis-associated acute kidney injury (SA-AKI) presents a severe challenge in the elderly due to increasing incidence, high mortality, and the lack of specific effective treatments. Exploring novel and secure preventive and/or therapeutic approaches is critical and urgent. Berberine (BBR), an isoquinoline alkaloid with anti-inflammatory, antioxidant, and immunomodulatory properties, has shown beneficial effects in various kidney diseases. This study examined whether BBR could protect against SA-AKI in aged rats. Sepsis was induced in 26-month-old male Wistar rats by cecal ligation and puncture (CLP), either with or without BBR pretreatment. CLP induction led to SA-AKI, as indicated by elevated serum levels of malondialdehyde, tumor necrosis factor-alpha, urea nitrogen, creatinine, and neutrophil gelatinase-associated lipocalin (NGAL), along with histopathological features of kidney damage. Key indicators of kidney oxidative stress, mitochondrial dysfunction, apoptosis, and activations of the Toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB) signaling, including the nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP3) inflammasome pathway, were also elevated following CLP induction. BBR pretreatment substantially mitigated these adverse effects, suggesting that it protects against SA-AKI in aged rats by reducing oxidative stress, preserving mitochondrial integrity, and inhibiting key inflammatory pathways. These findings highlight the potential of BBR as a therapeutic agent for managing SA-AKI in elderly populations. Full article

(This article belongs to the Special Issue Oxidative Stress in Renal Health)

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13 pages, 808 KiB

Open AccessArticle

Curcumin Supplementation and Vascular and Cognitive Function in Chronic Kidney Disease: A Randomized Controlled Trial

by Colin J. Gimblet, Nicholas T. Kruse, Katharine Geasland, Jeni Michelson, Mingyao Sun, Patrick Ten Eyck, Cari Linkenmeyer, Safur Rehman Mandukhail, Matthew J. Rossman, Meenakshi Sambharia, Michel Chonchol, Manjula Kurella Tamura, Douglas Seals, Karin F. Hoth and Diana Jalal

Antioxidants 2024, 13(8), 983; https://doi.org/10.3390/antiox13080983 - 14 Aug 2024

Viewed by 1507

Abstract

Chronic kidney disease (CKD) increases the risk of cardiovascular disease and cognitive impairment. Curcumin is a polyphenol that improves vascular and cognitive function in older adults; however, its effects on vascular and cognitive function in patients with CKD are unknown. We hypothesized that curcumin supplementation would improve vascular and cognitive function in patients with CKD. Eighty-eight adults diagnosed with stage 3b or 4 CKD (aged 66 ± 8 years, 75% male) participated in a 12-month, randomized, double-blind, placebo-controlled study to test the effects of curcumin (Longvida^®, 2000 mg/day) on vascular and cognitive function. Our primary outcome was brachial artery flow-mediated dilation (FMD). Our secondary outcomes were nitroglycerin-mediated dilation, carotid–femoral pulse wave velocity (cfPWV), and cognitive function assessed via the NIH Toolbox Cognition Battery. At baseline, the mean estimated glomerular filtration rate was 34.7 ± 10.8, and the median albumin/creatinine ratio was 81.9 (9.7, 417.3). A total of 44% of participants had diabetes. Compared with placebo, 12 months of curcumin did not improve FMD (median change from baseline was −0.7 (−2.1, 1.1) and −0.1 (−1.5, 1.5) for curcumin and placebo, respectively, with p = 0.69). Similarly, there were no changes in nitroglycerin-mediated dilation, cfPWV, or cognitive outcomes. These results do not support chronic curcumin supplementation to improve vascular and cognitive function in patients with CKD. Full article

(This article belongs to the Special Issue Oxidative Stress in Renal Health)

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20 pages, 6613 KiB

Open AccessArticle

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

Cited by 2 | Viewed by 1448

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, 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

Open AccessArticle

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 - 8 Jan 2024

Cited by 2 | Viewed by 2128

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 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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20 pages, 2383 KiB

Open AccessReview

The Role of Antioxidant Transcription Factor Nrf2 and Its Activating Compounds in Systemic Lupus Erythematosus

by Lu Liu, Karina de Leeuw, Harry van Goor and Johanna Westra

Antioxidants 2024, 13(10), 1224; https://doi.org/10.3390/antiox13101224 - 11 Oct 2024

Viewed by 949

Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which kidney involvement, so-called lupus nephritis (LN), is common and one of the most severe manifestations. Oxidative stress (OS) may play a role in the pathogenesis of LN through the exacerbation of inflammation and immune cell dysfunction/dysregulation. Nuclear factor erythroid 2-related factor 2 (Nrf2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the NFE2L2 gene and is regarded as a central regulator of the antioxidative response. Nrf2-activating compounds have been shown to alleviate oxidative stress in cells and tissues of lupus-prone mice. Although the precise mechanisms of Nrf2 activation on the immune system in SLE remain to be elucidated, Nrf2-activating compounds are considered novel therapeutical options to suppress OS and thereby might alleviate disease activity in SLE, especially in LN. This review therefore summarizes the role of the Nrf2 signaling pathway in the pathogenesis of SLE with LN and describes compounds modulating this pathway as potential additional clinical interventions. Full article

(This article belongs to the Special Issue Oxidative Stress in Renal Health)

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14 pages, 1370 KiB

Open AccessReview

Reactive Oxygen Species in Cystic Kidney Disease

by Sanat Subhash, Sonya Vijayvargiya, Aetan Parmar, Jazlyn Sandhu, Jabrina Simmons and Rupesh Raina

Antioxidants 2024, 13(10), 1186; https://doi.org/10.3390/antiox13101186 - 30 Sep 2024

Viewed by 1211

Abstract

Polycystic kidney disease (PKD) is a rare but significant renal condition with major implications for global acute and chronic patient care. Oxidative stress and reactive oxygen species (ROS) can significantly alter its pathophysiology, clinical outcomes, and treatment, contributing to negative outcomes, including hypertension, chronic kidney disease, and kidney failure. Inflammation from ROS and existing cysts propagate the generation and accumulation of ROS, exacerbating kidney injury, pro-fibrotic signaling cascades, and interstitial fibrosis. Early identification and prevention of oxidative stress and ROS can contribute to reduced cystic kidney disease progression and improved longitudinal patient outcomes. Increased research regarding biomarkers, the pathophysiology of oxidative stress, and novel therapeutic interventions alongside the creation of comprehensive guidelines establishing methods of assessment, monitoring, and intervention for oxidative stress in cystic kidney disease patients is imperative to standardize clinical practice and improve patient outcomes. The integration of artificial intelligence (AI), genetic editing, and genome sequencing could further improve the early detection and management of cystic kidney disease and mitigate adverse patient outcomes. In this review, we aim to comprehensively assess the multifactorial role of ROS in cystic kidney disease, analyzing its pathophysiology, clinical outcomes, treatment interventions, clinical trials, animal models, and future directions for patient care. Full article

(This article belongs to the Special Issue Oxidative Stress in Renal Health)

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40 pages, 1552 KiB

Open AccessReview

Potentials of Natural Antioxidants in Reducing Inflammation and Oxidative Stress in Chronic Kidney Disease

by On Ying Angela Lee, Alex Ngai Nick Wong, Ching Yan Ho, Ka Wai Tse, Angela Zaneta Chan, George Pak-Heng Leung, Yiu Wa Kwan and Martin Ho Yin Yeung

Antioxidants 2024, 13(6), 751; https://doi.org/10.3390/antiox13060751 - 20 Jun 2024

Cited by 3 | Viewed by 2741

Abstract

Chronic kidney disease (CKD) presents a substantial global public health challenge, with high morbidity and mortality. CKD patients often experience dyslipidaemia and poor glycaemic control, further exacerbating inflammation and oxidative stress in the kidney. If left untreated, these metabolic symptoms can progress to end-stage renal disease, necessitating long-term dialysis or kidney transplantation. Alleviating inflammation responses has become the standard approach in CKD management. Medications such as statins, metformin, and GLP-1 agonists, initially developed for treating metabolic dysregulation, demonstrate promising renal therapeutic benefits. The rising popularity of herbal remedies and supplements, perceived as natural antioxidants, has spurred investigations into their potential efficacy. Notably, lactoferrin, Boerhaavia diffusa, Amauroderma rugosum, and Ganoderma lucidum are known for their anti-inflammatory and antioxidant properties and may support kidney function preservation. However, the mechanisms underlying the effectiveness of Western medications and herbal remedies in alleviating inflammation and oxidative stress occurring in renal dysfunction are not completely known. This review aims to provide a comprehensive overview of CKD treatment strategies and renal function preservation and critically discusses the existing literature’s limitations whilst offering insight into the potential antioxidant effects of these interventions. This could provide a useful guide for future clinical trials and facilitate the development of effective treatment strategies for kidney functions. Full article

(This article belongs to the Special Issue Oxidative Stress in Renal Health)

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19 pages, 1269 KiB

Open AccessReview

Role of Uremic Toxins, Oxidative Stress, and Renal Fibrosis in Chronic Kidney Disease

by Weronika Frąk, Bartłomiej Dąbek, Marta Balcerczyk-Lis, Jakub Motor, Ewa Radzioch, Ewelina Młynarska, Jacek Rysz and Beata Franczyk

Antioxidants 2024, 13(6), 687; https://doi.org/10.3390/antiox13060687 - 3 Jun 2024

Viewed by 1894

Abstract

Affecting millions of people worldwide, chronic kidney disease is a serious medical problem. It results in a decrease in glomerular filtration rate below 60 mL/min/1.73 m, albuminuria, abnormalities in urine sediment and pathologies detected by imaging studies lasting a minimum of 3 months. Patients with CKD develop uremia, and as a result of the accumulation of uremic toxins in the body, patients can be expected to suffer from a number of medical consequences such as progression of CKD with renal fibrosis, development of atherosclerosis or increased incidence of cardiovascular events. Another key element in the pathogenesis of CKD is oxidative stress, resulting from an imbalance between the production of antioxidants and the production of reactive oxygen species. Oxidative stress contributes to damage to cellular proteins, lipids and DNA and increases inflammation, perpetuating kidney dysfunction. Additionally, renal fibrogenesis involving the accumulation of fibrous tissue in the kidneys occurs. In our review, we also included examples of forms of therapy for CKD. To improve the condition of CKD patients, pharmacotherapy can be used, as described in our review. Among the drugs that improve the prognosis of patients with CKD, we can include: GLP-1 analogues, SGLT2 inhibitors, Finerenone monoclonal antibody—Canakinumab and Sacubitril/Valsartan. Full article

(This article belongs to the Special Issue Oxidative Stress in Renal Health)

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45 pages, 1651 KiB

Open AccessReview

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

Cited by 11 | Viewed by 3666

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 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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