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Special Issue "Redox Imbalance and Mitochondrial Abnormalities in Kidney Disease"

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (15 December 2021) | Viewed by 28744

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Dr. Liang-Jun Yan

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Department of Pharmaceutical Sciences, College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
Interests: redox imbalance; oxidative stress; neuroprotection; diabetes; mitochondrial dysfunction; protein oxidation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The kidney performs important functions in our body and can inflict either acute kidney injury (AKI) or chronic kidney disease (CKD). AKI could be induced by kidney ischemia, by drugs such as cisplatin, and by heavy metals such as cadmium and arsenic. CKD could be induced by drugs, heavy metals, hypertension and diabetes as well as cancer. Importantly, nearly all kidney disorders have been shown to involve redox imbalance, reductive stress, oxidative stress, and mitochondrial abnormalities such as impaired mitochondrial homeostasis, including disrupted mitophagy and deranged mitochondrial unfolded protein response. Understanding how these redox-related dysregulated pathways may give us new insights into how to design novel approaches to fighting kidney disease.

This Special Issue will cover all topics related to AKI and CKD and will especially welcome submissions of manuscripts on redox mechanisms and pathophysiology underlying diabetic nephropathy or diabetic kidney disease (DKD) using all kinds of diabetic animal models. It should be noted that this Special Issue will consider publication of both review articles and original research articles.

Dr. Liang-Jun Yan
Guest Editor

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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. Biomolecules 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 2300 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

acute kidney injury
chronic kidney disease
diabetic nephropathy
diabetic kidney disease
redox imbalance
reductive stress
reactive oxygen species
oxidative stress
mitochondrial abnormalities
mitochondrial homeostasis
mitophagy
unfolded protein response

Related Special Issue

Redox Imbalance and Mitochondrial Abnormalities in Kidney Disease II in Biomolecules (5 articles)

Published Papers (12 papers)

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Editorial

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Open AccessEditorial

Redox Imbalance and Mitochondrial Abnormalities in Kidney Disease

Liang-Jun Yan

Biomolecules 2022, 12(3), 476; https://doi.org/10.3390/biom12030476 - 21 Mar 2022

Viewed by 1526

Abstract

The kidneys carry out fundamental life-sustaining functions by removing waste substances, controlling salt and water balance, retaining substances vital to the body such as glucose and proteins, and maintaining blood pH balance [...] Full article

(This article belongs to the Special Issue Redox Imbalance and Mitochondrial Abnormalities in Kidney Disease)

Research

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Open AccessArticle

Preservation of Mitochondrial Coupling and Renal Function by Controlled Oxygenated Rewarming of Porcine Kidney Grafts

Hristo Zlatev

Charlotte von Horn

and

Thomas Minor

Biomolecules 2021, 11(12), 1880; https://doi.org/10.3390/biom11121880 - 14 Dec 2021

Cited by 6 | Viewed by 1481

Abstract

Background: Warm reperfusion after previous cold storage has been shown to have a negative impact on mitochondrial function of organ grafts. Here, we wanted to investigate whether a more controlled warming up of the cold graft by ex vivo machine perfusion with gradually elevated temperature from cold to normothermia (including comparison of two warming up protocols) prior to implantation would be effective in preventing mitochondrial dysfunction upon reperfusion. Methods: All experiments were conducted on porcine kidneys retrieved 15 min after cardiac arrest. After 18 h of cold storage in HTK solution (CS, n = 6), kidneys (n = 6) were subjected to 2 h of reconditioning machine perfusion starting with a hypothermic period followed by a gradual increase in perfusion temperature up to 35 °C (controlled oxygenated rewarming—COR). For a second group (n = 6), the slow warming up was begun instantly after connecting the graft onto the machine (iCOR). Functional recovery of all grafts was then observed upon normothermic reperfusion in vitro. At the conclusion of the experiments, tissue specimens were taken for immediate isolation and analysis of renal mitochondria. Results: COR resulted in a significantly and more than 3-fold increased glomerular filtration rate upon reperfusion, along with a significant higher tubular sodium reabsorption and lesser loss of glucose in comparison to the controls. Enzyme release (AST) was also massively reduced during the reperfusion period. Specific analysis at the mitochondrial level revealed significantly better coupling efficiency and spare respiratory capacity in the COR group compared to the cold storage group. Interestingly, additional experiments revealed that the omission of a hypothermic perfusion period did not deteriorate any of the results after COR, provided that the instant temperature increase from 10 to 35 °C was effectuated in the same controlled manner. Conclusion: Controlled rewarming after extended cold preservation effectively improves mitochondrial recovery upon reperfusion and early functional outcome of kidney grafts. Full article

(This article belongs to the Special Issue Redox Imbalance and Mitochondrial Abnormalities in Kidney Disease)

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Open AccessArticle

Elevated Levels of Renalase, the β-NAD(P)H Isomerase, Can Be Used as Risk Factors of Major Adverse Cardiovascular Events and All-Cause Death in Patients with Chronic Kidney Disease

Wojciech Knop

Natalia Maria Serwin

Elżbieta Cecerska-Heryć

Bartłomiej Grygorcewicz

Barbara Dołęgowska

Aleksandra Gomółka

Magda Wiśniewska

and

Kazimierz Ciechanowski

Biomolecules 2021, 11(10), 1514; https://doi.org/10.3390/biom11101514 - 14 Oct 2021

Cited by 4 | Viewed by 1124

Abstract

Background: Renalase is an enzyme and a cytokine involved in cell survival. Since its discovery, associations between it and both cardiovascular and kidney disease have been noted. Recognizing this, we conducted a study in which we followed patients with chronic kidney disease. Material and methods: The study involved 90 CKD patients with varying stages of the disease and 30 healthy controls. Renalase was measured with an ELISA kit, and patients were followed-up after a median of 18 months. During the follow-up, we asked about the occurrence of MACE, all-cause mortality and the need for dialysis initiation. Results: In CKD subgroups, RNSL correlated with all-cause death only in the HD group (Rs = 0.49, p < 0.01). In the whole CKD population, we found a positive correlation of RNSL concentration and both MACE occurrence (Rs = 0.38, p < 0.001) and all-cause death (Rs = 0.34, p < 0.005). There was a significant increase in MACE occurrence probability in patients with elevated renalase levels (>25 μg/mL). Conclusions: Elevated renalase levels can be used as a risk factor of MACE in patients with CKD, but its long-term utility needs further research. High renalase levels are a risk factor of death among CKD patients. In HD patients, all deaths were observed among patients with >30 μg/mL; this level could be used as a “red flag” marker in future studies. Full article

(This article belongs to the Special Issue Redox Imbalance and Mitochondrial Abnormalities in Kidney Disease)

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Open AccessArticle

Protective Effects of Purple Rice Husk against Diabetic Nephropathy by Modulating PGC-1α/SIRT3/SOD2 Signaling and Maintaining Mitochondrial Redox Equilibrium in Rats

Orawan Wongmekiat

Narissara Lailerd

Anongporn Kobroob

and

Wachirasek Peerapanyasut

Biomolecules 2021, 11(8), 1224; https://doi.org/10.3390/biom11081224 - 17 Aug 2021

Cited by 11 | Viewed by 1893

Abstract

Diabetic nephropathy (DN) is the primary cause of end-stage renal disease worldwide. Oxidative stress and mitochondrial dysfunction are central to its pathogenesis. Rice husk, the leftover from the milling process, is a good source of phytochemicals with antioxidant activity. This study evaluated the possible protection of purple rice husk extract (PRHE) against diabetic kidney injury. Type 2 diabetic rats were given vehicle, PRHE, metformin, and PRHE+metformin, respectively, while nondiabetic rats received vehicle. After 12 weeks, diabetic rats developed nephropathy as proven by metabolic alterations (increased blood glucose, insulin, HOMA-IR, triglycerides, cholesterol) and renal abnormalities (podocyte injury, microalbuminuria, increased serum creatinine, decreased creatinine clearance). Treatment with PRHE, metformin, or combination diminished these changes, improved mitochondrial function (decreased mitochondrial swelling, reactive oxygen species production, membrane potential changes), and reduced renal oxidative damage (decreased lipid peroxidation and increased antioxidants). Increased expression of PGC-1α, SIRT3, and SOD2 and decreased expression of Ac-SOD2 correlated with the beneficial outcomes. HPLC revealed protocatechuic acid and cyanidin-3-glucoside as the key components of PRHE. The findings indicate that PRHE effectively protects against the development of DN by retaining mitochondrial redox equilibrium via the regulation of PGC-1α-SIRT3-SOD2 signaling. This study creates an opportunity to develop this agricultural waste into a useful health product for diabetes. Full article

(This article belongs to the Special Issue Redox Imbalance and Mitochondrial Abnormalities in Kidney Disease)

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Open AccessArticle

Suppression of Inflammation-Associated Kidney Damage Post-Transplant Using the New PrC-210 Free Radical Scavenger in Rats

Maya M. Coumbe Gitter

and

William E. Fahl

Biomolecules 2021, 11(7), 1054; https://doi.org/10.3390/biom11071054 - 19 Jul 2021

Cited by 3 | Viewed by 1818

Abstract

Allograft kidney transplantation, which triggers host cellular- and antibody-mediated rejection of the kidney, is a major contributor to kidney damage during transplant. Here, we asked whether PrC-210 would suppress damage seen in allograft kidney transplant. Brown Norway (BN) rat kidneys were perfused in situ (UW Solution) with or without added 30 mM PrC-210, and then immediately transplanted into Lewis (LEW) rats. 20 h later, the transplanted BN kidneys and LEW rat plasma were analyzed. Kidney histology, and kidney/serum levels of several inflammation-associated cytokines, were measured to assess mismatch-related kidney pathology, and PrC-210 protective efficacy. Twenty hours after the allograft transplants: (i) significant histologic kidney tubule damage and mononuclear inflammatory cell infiltration were seen in allograft kidneys; (ii) kidney function metrics (creatinine and BUN) were significantly elevated; (iii) significant changes in key cytokines, i.e., TIMP-1, TNF-alpha and MIP-3A/CCL20, and kidney activated caspase levels were seen. In PrC-210-treated kidneys and recipient rats, (i) kidney histologic damage (Banff Scores) and mononuclear infiltration were reduced to untreated background levels; (ii) creatinine and BUN were significantly reduced; and (iii) activated caspase and cytokine changes were significantly reduced, some to background. In conclusion, the results suggest that PrC-210 could provide broadly applicable organ protection for many allograft transplantation conditions; it could protect transplanted kidneys during and after all stages of the transplantation process—from organ donation, through transportation, re-implantation and the post-operative inflammation—to minimize acute and chronic rejection. Full article

(This article belongs to the Special Issue Redox Imbalance and Mitochondrial Abnormalities in Kidney Disease)

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Review

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Mitochondrial Oxidative Stress and Cell Death in Podocytopathies

and

Biomolecules 2022, 12(3), 403; https://doi.org/10.3390/biom12030403 - 04 Mar 2022

Cited by 3 | Viewed by 1673

Abstract

Podocytopathies are kidney diseases that are driven by podocyte injury with proteinuria and proteinuria-related symptoms as the main clinical presentations. Albeit podocytopathies are the major contributors to end-stage kidney disease, the underlying molecular mechanisms of podocyte injury remain to be elucidated. Mitochondrial oxidative stress is associated with kidney diseases, and increasing evidence suggests that oxidative stress plays a vital role in the pathogenesis of podocytopathies. Accumulating evidence has placed mitochondrial oxidative stress in the focus of cell death research. Excessive generated reactive oxygen species over antioxidant defense under pathological conditions lead to oxidative damage to cellular components and regulate cell death in the podocyte. Conversely, exogenous antioxidants can protect podocyte from cell death. This review provides an overview of the role of mitochondrial oxidative stress in podocytopathies and discusses its role in the cell death of the podocyte, aiming to identify the novel targets to improve the treatment of patients with podocytopathies. Full article

(This article belongs to the Special Issue Redox Imbalance and Mitochondrial Abnormalities in Kidney Disease)

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Open AccessEditor’s ChoiceReview

Glucose- and Non-Glucose-Induced Mitochondrial Dysfunction in Diabetic Kidney Disease

Marie Ito

Margaret Zvido Gurumani

Sandra Merscher

and

Alessia Fornoni

Biomolecules 2022, 12(3), 351; https://doi.org/10.3390/biom12030351 - 23 Feb 2022

Cited by 5 | Viewed by 1868

Abstract

Mitochondrial dysfunction plays an important role in the pathogenesis and progression of diabetic kidney disease (DKD). In this review, we will discuss mitochondrial dysfunction observed in preclinical models of DKD as well as in clinical DKD with a focus on oxidative phosphorylation (OXPHOS), mitochondrial reactive oxygen species (mtROS), biogenesis, fission and fusion, mitophagy and urinary mitochondrial biomarkers. Both glucose- and non-glucose-induced mitochondrial dysfunction will be discussed. In terms of glucose-induced mitochondrial dysfunction, the energetic shift from OXPHOS to aerobic glycolysis, called the Warburg effect, occurs and the resulting toxic intermediates of glucose metabolism contribute to DKD-induced injury. In terms of non-glucose-induced mitochondrial dysfunction, we will review the roles of lipotoxicity, hypoxia and vasoactive pathways, including endothelin-1 (Edn1)/Edn1 receptor type A signaling pathways. Although the relative contribution of each of these pathways to DKD remains unclear, the goal of this review is to highlight the complexity of mitochondrial dysfunction in DKD and to discuss how markers of mitochondrial dysfunction could help us stratify patients at risk for DKD. Full article

(This article belongs to the Special Issue Redox Imbalance and Mitochondrial Abnormalities in Kidney Disease)

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Open AccessEditor’s ChoiceReview

Antioxidant Roles of SGLT2 Inhibitors in the Kidney

Carmen Llorens-Cebrià

Mireia Molina-Van den Bosch

Ander Vergara

Conxita Jacobs-Cachá

and

Maria José Soler

Biomolecules 2022, 12(1), 143; https://doi.org/10.3390/biom12010143 - 16 Jan 2022

Cited by 6 | Viewed by 2054

Abstract

The reduction-oxidation (redox) system consists of the coupling and coordination of various electron gradients that are generated thanks to serial reduction-oxidation enzymatic reactions. These reactions happen in every cell and produce radical oxidants that can be mainly classified into reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS and RNS modulate cell-signaling pathways and cellular processes fundamental to normal cell function. However, overproduction of oxidative species can lead to oxidative stress (OS) that is pathological. Oxidative stress is a main contributor to diabetic kidney disease (DKD) onset. In the kidney, the proximal tubular cells require a high energy supply to reabsorb proteins, metabolites, ions, and water. In a diabetic milieu, glucose-induced toxicity promotes oxidative stress and mitochondrial dysfunction, impairing tubular function. Increased glucose level in urine and ROS enhance the activity of sodium/glucose co-transporter type 2 (SGLT2), which in turn exacerbates OS. SGLT2 inhibitors have demonstrated clear cardiovascular benefits in DKD which may be in part ascribed to the generation of a beneficial equilibrium between oxidant and antioxidant mechanisms. Full article

(This article belongs to the Special Issue Redox Imbalance and Mitochondrial Abnormalities in Kidney Disease)

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Open AccessFeature PaperReview

Cadmium-Induced Kidney Injury: Oxidative Damage as a Unifying Mechanism

Liang-Jun Yan

and

Daniel C. Allen

Biomolecules 2021, 11(11), 1575; https://doi.org/10.3390/biom11111575 - 23 Oct 2021

Cited by 32 | Viewed by 3705

Abstract

Cadmium is a nonessential metal that has heavily polluted the environment due to human activities. It can be absorbed into the human body via the gastrointestinal tract, respiratory tract, and the skin, and can cause chronic damage to the kidneys. The main site where cadmium accumulates and causes damage within the nephrons is the proximal tubule. This accumulation can induce dysfunction of the mitochondrial electron transport chain, leading to electron leakage and production of reactive oxygen species (ROS). Cadmium may also impair the function of NADPH oxidase, resulting in another source of ROS. These ROS together can cause oxidative damage to DNA, proteins, and lipids, triggering epithelial cell death and a decline in kidney function. In this article, we also reviewed evidence that the antioxidant power of plant extracts, herbal medicines, and pharmacological agents could ameliorate cadmium-induced kidney injury. Finally, a model of cadmium-induced kidney injury, centering on the notion that oxidative damage is a unifying mechanism of cadmium renal toxicity, is also presented. Given that cadmium exposure is inevitable, further studies using animal models are warranted for a detailed understanding of the mechanism underlying cadmium induced ROS production, and for the identification of more therapeutic targets. Full article

(This article belongs to the Special Issue Redox Imbalance and Mitochondrial Abnormalities in Kidney Disease)

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Open AccessReview

Involvement of Tricarboxylic Acid Cycle Metabolites in Kidney Diseases

Alexis Paulina Jiménez-Uribe

Estefani Yaquelin Hernández-Cruz

Karla Jaqueline Ramírez-Magaña

and

José Pedraza-Chaverri

Biomolecules 2021, 11(9), 1259; https://doi.org/10.3390/biom11091259 - 24 Aug 2021

Cited by 7 | Viewed by 2621

Abstract

Mitochondria are complex organelles that orchestrate several functions in the cell. The primary function recognized is energy production; however, other functions involve the communication with the rest of the cell through reactive oxygen species (ROS), calcium influx, mitochondrial DNA (mtDNA), adenosine triphosphate (ATP) levels, cytochrome c release, and also through tricarboxylic acid (TCA) metabolites. Kidney function highly depends on mitochondria; hence mitochondrial dysfunction is associated with kidney diseases. In addition to oxidative phosphorylation impairment, other mitochondrial abnormalities have been described in kidney diseases, such as induction of mitophagy, intrinsic pathway of apoptosis, and releasing molecules to communicate to the rest of the cell. The TCA cycle is a metabolic pathway whose primary function is to generate electrons to feed the electron transport system (ETS) to drives energy production. However, TCA cycle metabolites can also release from mitochondria or produced in the cytosol to exert different functions and modify cell behavior. Here we review the involvement of some of the functions of TCA metabolites in kidney diseases. Full article

(This article belongs to the Special Issue Redox Imbalance and Mitochondrial Abnormalities in Kidney Disease)

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Open AccessReview

Mitochondrial Redox Signaling and Oxidative Stress in Kidney Diseases

Ana Karina Aranda-Rivera

Alfredo Cruz-Gregorio

Omar Emiliano Aparicio-Trejo

and

José Pedraza-Chaverri

Biomolecules 2021, 11(8), 1144; https://doi.org/10.3390/biom11081144 - 03 Aug 2021

Cited by 32 | Viewed by 3964

Abstract

Mitochondria are essential organelles in physiology and kidney diseases, because they produce cellular energy required to perform their function. During mitochondrial metabolism, reactive oxygen species (ROS) are produced. ROS function as secondary messengers, inducing redox-sensitive post-translational modifications (PTM) in proteins and activating or deactivating different cell signaling pathways. However, in kidney diseases, ROS overproduction causes oxidative stress (OS), inducing mitochondrial dysfunction and altering its metabolism and dynamics. The latter processes are closely related to changes in the cell redox-sensitive signaling pathways, causing inflammation and apoptosis cell death. Although mitochondrial metabolism, ROS production, and OS have been studied in kidney diseases, the role of redox signaling pathways in mitochondria has not been addressed. This review focuses on altering the metabolism and dynamics of mitochondria through the dysregulation of redox-sensitive signaling pathways in kidney diseases. Full article

(This article belongs to the Special Issue Redox Imbalance and Mitochondrial Abnormalities in Kidney Disease)

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Open AccessReview

NADH/NAD⁺ Redox Imbalance and Diabetic Kidney Disease

Liang-Jun Yan

Biomolecules 2021, 11(5), 730; https://doi.org/10.3390/biom11050730 - 14 May 2021

Cited by 12 | Viewed by 3213

Abstract

Diabetic kidney disease (DKD) is a common and severe complication of diabetes mellitus. If left untreated, DKD can advance to end stage renal disease that requires either dialysis or kidney replacement. While numerous mechanisms underlie the pathogenesis of DKD, oxidative stress driven by NADH/NAD⁺ redox imbalance and mitochondrial dysfunction have been thought to be the major pathophysiological mechanism of DKD. In this review, the pathways that increase NADH generation and those that decrease NAD⁺ levels are overviewed. This is followed by discussion of the consequences of NADH/NAD⁺ redox imbalance including disruption of mitochondrial homeostasis and function. Approaches that can be applied to counteract DKD are then discussed, which include mitochondria-targeted antioxidants and mimetics of superoxide dismutase, caloric restriction, plant/herbal extracts or their isolated compounds. Finally, the review ends by pointing out that future studies are needed to dissect the role of each pathway involved in NADH-NAD⁺ metabolism so that novel strategies to restore NADH/NAD⁺ redox balance in the diabetic kidney could be designed to combat DKD. Full article

(This article belongs to the Special Issue Redox Imbalance and Mitochondrial Abnormalities in Kidney Disease)

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