The Role of Redox Signaling in Kidney Physiology and 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 (20 November 2022) | Viewed by 18587

Special Issue Editors

1. Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark
2. Department of Nephrology, Odense University Hospital, 5000 Odense, Denmark
Interests: chronic kidney disease; oxidative stress; antioxidants; vitamin D; cell signaling

Special Issue Information

Dear Colleagues,

Kidney diseases present a worldwide health problem and are associated with a high burden of morbidity and mortality. There is an urgent need for novel therapies, and redox-based therapeutic strategies (“redox medicine”) are regarded as promising tools to reduce the progression of renal decline and the development of kidney disease-related morbidity.  

The kidney depends on redox signaling to realize its function and a considerable number of proteins are redox-sensitive. Both acute and chronic kidney disease are associated with an imbalance between antioxidants and oxidants that is in favour of the latter. The resulting state with molecular damage and/or a disturbance of the physiologic redox signaling is termed “oxidative stress”. Recent research has advanced our understanding of redox signaling in kidney disease states, but therapies targeting specific redox signaling pathways are not yet available for clinical routine. The search for therapeutic options is complicated by the inevitable requirement of efficient redox signaling as part of the physiological regulation in the kidney and in the body as a whole.

Therefore, we welcome submissions to a Special Issue entitled “The Role of Redox Signaling in Kidney Physiology and Kidney Disease”, to further advance our understanding in this area. Hopefully, this will help to pave the way for new therapeutic strategies in kidney diseases.

Dr. Alexandra Scholze
Prof. Dr. José Pedraza Chaverri
Guest Editors

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Keywords

  • redox signaling
  • oxidative stress
  • kidney physiology
  • kidney disease
  • redox-based therapeutic strategies

Published Papers (6 papers)

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Research

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13 pages, 592 KiB  
Article
In Patients with Chronic Kidney Disease Advanced Glycation End-Products Receptors Isoforms (sRAGE and esRAGE) Are Associated with Malnutrition
Antioxidants 2022, 11(7), 1253; https://doi.org/10.3390/antiox11071253 - 25 Jun 2022
Cited by 4 | Viewed by 1803
Abstract
Background: in patients with chronic kidney disease (CKD), the inflammatory and pro-oxidant milieu may contribute to malnutrition development. In this study, we investigated the relationship between inflammation, advanced glycation end-products (AGEs), and their receptors (RAGEs) with malnutrition in CKD patients. Methods: we evaluated [...] Read more.
Background: in patients with chronic kidney disease (CKD), the inflammatory and pro-oxidant milieu may contribute to malnutrition development. In this study, we investigated the relationship between inflammation, advanced glycation end-products (AGEs), and their receptors (RAGEs) with malnutrition in CKD patients. Methods: we evaluated 117 patients. AGEs were quantified by fluorescence intensity using a fluorescence spectrophotometer, soluble RAGEs isoforms, and inflammatory interleukins by ELISA. Malnutrition was assessed by a malnutrition inflammation score. Results: mean age was 80 ± +11 years, eGFR was 25 ± +11 mL/min/1.73 m2 and BMI was 28 ± 5 Kg/m2. Malnourished individuals were older, had lower estimated protein intake (nPCR 0.65 ± 0.2 vs. 0.8 ± 0.2 vs. 0.8 ± 0.3, p = 0.01), higher C reactive protein (CRP 0.6 ± 1 vs. 0.6 ± 0.7 vs. 0.17 ± 0.13, p = 0.02) and tumor necrosis factor α (TNF α 14.7 ± 8.7 vs. 15.6 ± 8 vs. 11.8 ± 5.8, p = 0.029). Malnourished patients had higher sRAGE (2813 ± 1477 vs. 2158 ± 1236 vs. 2314 ± 1115, p = 0.035) and esRAGE (648 [408–1049] vs. 476 [355–680] vs. 545 [380–730] p = 0.033). In the multivariate analysis, only sRAGE maintained its association with malnutrition (p = 0.02) independently of aging and inflammation. Conclusions: in CKD patients, RAGEs isoforms, but not AGEs, are associated with malnutrition, irrespective of systemic inflammation, aging, and renal function. Full article
(This article belongs to the Special Issue The Role of Redox Signaling in Kidney Physiology and Kidney Disease)
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10 pages, 1692 KiB  
Article
Enhanced Oxidative DNA-Damage in Peritoneal Dialysis Patients via the TXNIP/TRX Axis
Antioxidants 2022, 11(6), 1124; https://doi.org/10.3390/antiox11061124 - 06 Jun 2022
Cited by 2 | Viewed by 1748
Abstract
Peritoneal dialysis (PD) is an effective method of renal replacement therapy, providing a high level of patient autonomy. Nevertheless, the long-term use of PD is limited due to deleterious effects of PD fluids to the structure and function of the peritoneal membrane leading [...] Read more.
Peritoneal dialysis (PD) is an effective method of renal replacement therapy, providing a high level of patient autonomy. Nevertheless, the long-term use of PD is limited due to deleterious effects of PD fluids to the structure and function of the peritoneal membrane leading to loss of dialysis efficacy. PD patients show excessive oxidative stress compared to controls or chronic kidney disease (CKD) patients not on dialysis. Therefore, defense systems against detrimental events play a pivotal role in the integrity of the peritoneal membrane. The thioredoxin-interacting-protein (TXNIP)/thioredoxin (TRX) system also plays a major role in maintaining the redox homeostasis. We hypothesized that the upregulation of TXNIP negatively influences TRX activity, resulting in enhanced oxidative DNA-damage in PD patients. Therefore, we collected plasma samples and human peritoneal biopsies of healthy controls and PD patients as well. Using ELISA-analysis and immunohistochemistry, we showed that PD patients had elevated TXNIP levels compared to healthy controls. Furthermore, we demonstrated that PD patients had a reduced TRX activity, thereby leading to increased oxidative DNA-damage. Hence, targeting the TXNIP/TRX system as well as the use of oxidative stress scavengers could become promising therapeutic approaches potentially applicable in clinical practice in order to sustain and improve peritoneal membrane function. Full article
(This article belongs to the Special Issue The Role of Redox Signaling in Kidney Physiology and Kidney Disease)
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Review

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14 pages, 946 KiB  
Review
Redox Signaling in Chronic Kidney Disease-Associated Cachexia
Antioxidants 2023, 12(4), 945; https://doi.org/10.3390/antiox12040945 - 18 Apr 2023
Cited by 1 | Viewed by 1161
Abstract
Redox signaling alterations contribute to chronic kidney disease (CKD)-associated cachexia. This review aims to summarize studies about redox pathophysiology in CKD-associated cachexia and muscle wasting and to discuss potential therapeutic approaches based on antioxidant and anti-inflammatory molecules to restore redox homeostasis. Enzymatic and [...] Read more.
Redox signaling alterations contribute to chronic kidney disease (CKD)-associated cachexia. This review aims to summarize studies about redox pathophysiology in CKD-associated cachexia and muscle wasting and to discuss potential therapeutic approaches based on antioxidant and anti-inflammatory molecules to restore redox homeostasis. Enzymatic and non-enzymatic systems of antioxidant molecules have been studied in experimental models of kidney diseases and patients with CKD. Oxidative stress is increased by several factors present in CKD, including uremic toxins, inflammation, and metabolic and hormone alterations, leading to muscle wasting. Rehabilitative nutritional and physical exercises have shown beneficial effects for CKD-associated cachexia. Anti-inflammatory molecules have also been tested in experimental models of CKD. The importance of oxidative stress has been shown by experimental studies in which antioxidant therapies ameliorated CKD and its associated complications in the 5/6 nephrectomy model. Treatment of CKD-associated cachexia is a challenge and further studies are necessary to investigate potential therapies involving antioxidant therapy. Full article
(This article belongs to the Special Issue The Role of Redox Signaling in Kidney Physiology and Kidney Disease)
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30 pages, 3249 KiB  
Review
Nrf2 Activation in Chronic Kidney Disease: Promises and Pitfalls
Antioxidants 2022, 11(6), 1112; https://doi.org/10.3390/antiox11061112 - 03 Jun 2022
Cited by 18 | Viewed by 4410
Abstract
The nuclear factor erythroid 2-related factor 2 (Nrf2) protects the cell against oxidative damage. The Nrf2 system comprises a complex network that functions to ensure adequate responses to redox perturbations, but also metabolic demands and cellular stresses. It must be kept within a [...] Read more.
The nuclear factor erythroid 2-related factor 2 (Nrf2) protects the cell against oxidative damage. The Nrf2 system comprises a complex network that functions to ensure adequate responses to redox perturbations, but also metabolic demands and cellular stresses. It must be kept within a physiologic activity range. Oxidative stress and alterations in Nrf2-system activity are central for chronic-kidney-disease (CKD) progression and CKD-related morbidity. Activation of the Nrf2 system in CKD is in multiple ways related to inflammation, kidney fibrosis, and mitochondrial and metabolic effects. In human CKD, both endogenous Nrf2 activation and repression exist. The state of the Nrf2 system varies with the cause of kidney disease, comorbidities, stage of CKD, and severity of uremic toxin accumulation and inflammation. An earlier CKD stage, rapid progression of kidney disease, and inflammatory processes are associated with more robust Nrf2-system activation. Advanced CKD is associated with stronger Nrf2-system repression. Nrf2 activation is related to oxidative stress and moderate uremic toxin and nuclear factor kappa B (NF-κB) elevations. Nrf2 repression relates to high uremic toxin and NF-κB concentrations, and may be related to Kelch-like ECH-associated protein 1 (Keap1)-independent Nrf2 degradation. Furthermore, we review the effects of pharmacological Nrf2 activation by bardoxolone methyl, curcumin, and resveratrol in human CKD and outline strategies for how to adapt future Nrf2-targeted therapies to the requirements of patients with CKD. Full article
(This article belongs to the Special Issue The Role of Redox Signaling in Kidney Physiology and Kidney Disease)
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28 pages, 5782 KiB  
Review
Extracellular Vesicles in Redox Signaling and Metabolic Regulation in Chronic Kidney Disease
Antioxidants 2022, 11(2), 356; https://doi.org/10.3390/antiox11020356 - 11 Feb 2022
Cited by 9 | Viewed by 2967
Abstract
Chronic kidney disease (CKD) is a world health problem increasing dramatically. The onset of CKD is driven by several mechanisms; among them, metabolic reprogramming and changes in redox signaling play critical roles in the advancement of inflammation and the subsequent fibrosis, common pathologies [...] Read more.
Chronic kidney disease (CKD) is a world health problem increasing dramatically. The onset of CKD is driven by several mechanisms; among them, metabolic reprogramming and changes in redox signaling play critical roles in the advancement of inflammation and the subsequent fibrosis, common pathologies observed in all forms of CKD. Extracellular vesicles (EVs) are cell-derived membrane packages strongly associated with cell-cell communication since they transfer several biomolecules that serve as mediators in redox signaling and metabolic reprogramming in the recipient cells. Recent studies suggest that EVs, especially exosomes, the smallest subtype of EVs, play a fundamental role in spreading renal injury in CKD. Therefore, this review summarizes the current information about EVs and their cargos’ participation in metabolic reprogramming and mitochondrial impairment in CKD and their role in redox signaling changes. Finally, we analyze the effects of these EV-induced changes in the amplification of inflammatory and fibrotic processes in the progression of CKD. Furthermore, the data suggest that the identification of the signaling pathways involved in the release of EVs and their cargo under pathological renal conditions can allow the identification of new possible targets of injury spread, with the goal of preventing CKD progression. Full article
(This article belongs to the Special Issue The Role of Redox Signaling in Kidney Physiology and Kidney Disease)
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45 pages, 1545 KiB  
Review
Involvement of Inflammasome Components in Kidney Disease
Antioxidants 2022, 11(2), 246; https://doi.org/10.3390/antiox11020246 - 27 Jan 2022
Cited by 17 | Viewed by 4735
Abstract
Inflammasomes are multiprotein complexes with an important role in the innate immune response. Canonical activation of inflammasomes results in caspase-1 activation and maturation of cytokines interleukin-1β and -18. These cytokines can elicit their effects through receptor activation, both locally within a certain tissue [...] Read more.
Inflammasomes are multiprotein complexes with an important role in the innate immune response. Canonical activation of inflammasomes results in caspase-1 activation and maturation of cytokines interleukin-1β and -18. These cytokines can elicit their effects through receptor activation, both locally within a certain tissue and systemically. Animal models of kidney diseases have shown inflammasome involvement in inflammation, pyroptosis and fibrosis. In particular, the inflammasome component nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) and related canonical mechanisms have been investigated. However, it has become increasingly clear that other inflammasome components are also of importance in kidney disease. Moreover, it is becoming obvious that the range of molecular interaction partners of inflammasome components in kidney diseases is wide. This review provides insights into these current areas of research, with special emphasis on the interaction of inflammasome components and redox signalling, endoplasmic reticulum stress, and mitochondrial function. We present our findings separately for acute kidney injury and chronic kidney disease. As we strictly divided the results into preclinical and clinical data, this review enables comparison of results from those complementary research specialities. However, it also reveals that knowledge gaps exist, especially in clinical acute kidney injury inflammasome research. Furthermore, patient comorbidities and treatments seem important drivers of inflammasome component alterations in human kidney disease. Full article
(This article belongs to the Special Issue The Role of Redox Signaling in Kidney Physiology and Kidney Disease)
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