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17 pages, 6420 KiB

Open AccessArticle

Redox Metabolism and Vascular Calcification in Chronic Kidney Disease

by Natalia Carrillo-López, Sara Panizo, Beatriz Martín-Carro, Juan Carlos Mayo Barrallo, Pablo Román-García, Raúl García-Castro, Jesús María Fernández-Gómez, Miguel Ángel Hevia-Suárez, Julia Martín-Vírgala, Sara Fernández-Villabrille, Laura Martínez-Arias, Sara Barrio Vázquez, Laura Calleros Basilio, Manuel Naves-Díaz, Jorge Benito Cannata-Andía, Isabel Quirós-González, Cristina Alonso-Montes and José Luis Fernández-Martín

Biomolecules 2023, 13(9), 1419; https://0-doi-org.brum.beds.ac.uk/10.3390/biom13091419 - 20 Sep 2023

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Abstract

Vascular calcification (VC) is a common complication in patients with chronic kidney disease which increases their mortality. Although oxidative stress is involved in the onset and progression of this disorder, the specific role of some of the main redox regulators, such as catalase, [...] Read more.

Vascular calcification (VC) is a common complication in patients with chronic kidney disease which increases their mortality. Although oxidative stress is involved in the onset and progression of this disorder, the specific role of some of the main redox regulators, such as catalase, the main scavenger of H₂O₂, remains unclear. In the present study, epigastric arteries of kidney transplant recipients, a rat model of VC, and an in vitro model of VC exhibiting catalase (Cts) overexpression were analysed. Pericalcified areas of human epigastric arteries had increased levels of catalase and cytoplasmic, rather than nuclear runt-related transcription factor 2 (RUNX2). In the rat model, advanced aortic VC concurred with lower levels of the H₂O₂-scavenger glutathione peroxidase 3 compared to controls. In an early model of calcification using vascular smooth muscle cells (VSMCs), Cts VSMCs showed the expected increase in total levels of RUNX2. However, Cts VMSCs also exhibited a lower percentage of the nucleus stained for RUNX2 in response to calcifying media. In this early model of VC, we did not observe a dysregulation of the mitochondrial redox state; instead, an increase in the general redox state was observed in the cytoplasm. These results highlight the complex role of antioxidant enzymes as catalase by regulation of RUNX2 subcellular location delaying the onset of VC. Full article

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

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16 pages, 3958 KiB

Open AccessArticle

The Combined Administration of Vitamin C and Copper Induces a Systemic Oxidative Stress and Kidney Injury

by Rui Jiang, Yang Sui, Jingru Hong, Manabu Niimi, Qiaojing Yan, Zhuheng Shi and Jian Yao

Biomolecules 2023, 13(1), 143; https://0-doi-org.brum.beds.ac.uk/10.3390/biom13010143 - 10 Jan 2023

Cited by 1 | Viewed by 2750

Abstract

Vitamin C (ascorbic acid; AA) and copper (Cu²⁺) are well used supplements with many health-promoting actions. However, when they are used in combination, the Fenton reaction occurs, leading to the formation of highly reactive hydroxyl radicals. Given that kidney is vulnerable [...] Read more.

Vitamin C (ascorbic acid; AA) and copper (Cu²⁺) are well used supplements with many health-promoting actions. However, when they are used in combination, the Fenton reaction occurs, leading to the formation of highly reactive hydroxyl radicals. Given that kidney is vulnerable to many toxicants including free radicals, we speculated that the in vivo administration of AA plus Cu²⁺ may cause oxidative kidney injury. The purpose of this study was to address this possibility. Mice were administered with AA and Cu²⁺, alone or in combination, via oral gavage once a day for various periods. Changes in the systemic oxidative status, as well renal structure and functions, were examined. The administration of AA plus Cu²⁺ elevated protein oxidation in serum, intestine, bladder, and kidney, as evidenced by the increased sulfenic acid formation and decreased level of free sulfhydryl groups (-SH). The systemic oxidative stress induced by AA plus Cu²⁺ was associated with a significant loss of renal function and structure, as indicated by the increased blood urea nitrogen (BUN), creatinine and urinary proteins, as well as glomerular and tubular cell injury. These effects of AA and Cu²⁺ were only observed when used in combination, and could be entirely prevented by thiol antioxidant NAC. Further analysis using cultured renal tubular epithelial cells revealed that AA plus Cu²⁺ caused cellular protein oxidation and cell death, which could be abolished by NAC and catalase. Moreover, coincubation of AA and Cu²⁺ led to H₂O₂ production. Collectively, our study revealed that a combined administration of AA and Cu²⁺ resulted in systemic oxidative stress and renal cell injury. As health-promoting supplements, AA and Cu²⁺ should not be used together. Full article

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

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20 pages, 5836 KiB

Open AccessArticle

Role of Arginase-II in Podocyte Injury under Hypoxic Conditions

by Zhilong Ren, Duilio Michele Potenza, Yiqiong Ma, Guillaume Ajalbert, David Hoogewijs, Xiu-Fen Ming and Zhihong Yang

Biomolecules 2022, 12(9), 1213; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12091213 - 31 Aug 2022

Cited by 4 | Viewed by 1741

Abstract

Hypoxia plays a crucial role in acute and chronic renal injury, which is attributable to renal tubular and glomerular cell damage. Some studies provide evidence that hypoxia-dependent upregulation of the mitochondrial enzyme arginase type-II (Arg-II) in tubular cells promotes renal tubular injury. It [...] Read more.

Hypoxia plays a crucial role in acute and chronic renal injury, which is attributable to renal tubular and glomerular cell damage. Some studies provide evidence that hypoxia-dependent upregulation of the mitochondrial enzyme arginase type-II (Arg-II) in tubular cells promotes renal tubular injury. It is, however, not known whether Arg-II is also expressed in glomerular cells, particularly podocytes under hypoxic conditions, contributing to hypoxia-induced podocyte injury. The effects of hypoxia on human podocyte cells (AB8/13) in cultures and on isolated kidneys from wild-type (wt) and arg-ii gene-deficient (arg-ii^−/−) mice ex vivo, as well as on mice of the two genotypes in vivo, were investigated, respectively. We found that the Arg-II levels were enhanced in cultured podocytes in a time-dependent manner over 48 h, which was dependent on the stabilization of hypoxia-inducible factor 1α (HIF1α). Moreover, a hypoxia-induced derangement of cellular actin cytoskeletal fibers, a decrease in podocin, and an increase in mitochondrial ROS (mtROS) generation—as measured by MitoSOX—were inhibited by adenoviral-mediated arg-ii gene silencing. These effects of hypoxia on podocyte injury were mimicked by the HIFα stabilizing drug DMOG, which inhibits prolyl hydroxylases (PHD), the enzymes involved in HIFα degradation. The silencing of arg-ii prevented the detrimental effects of DMOG on podocytes. Furthermore, the inhibition of mtROS generation by rotenone—the inhibitor of respiration chain complex-I—recapitulated the protective effects of arg-ii silencing on podocytes under hypoxic conditions. Moreover, the ex vivo experiments with isolated kidney tissues and the in vivo experiments with mice exposed to hypoxic conditions showed increased Arg-II levels in podocytes and decreased podocyte markers regarding synaptopodin in wt mice but not in arg-ii^−/− mice. While age-associated albuminuria was reduced in the arg-ii^−/− mice, the hypoxia-induced increase in albuminuria was, however, not significantly affected in the arg-ii^−/−. Our study demonstrates that Arg-II in podocytes promotes cell injury. Arg-ii ablation seems insufficient to protect mice in vivo against a hypoxia-induced increase in albuminuria, but it does reduce albuminuria in aging. Full article

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

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18 pages, 4789 KiB

Open AccessArticle

Crocodile Oil Disrupts Mitochondrial Homeostasis and Exacerbates Diabetic Kidney Injury in Spontaneously Diabetic Torii Rats

by Thiri Wai Linn, Anongporn Kobroob, Metas Ngernjan, Doungporn Amornlerdpison, Narissara Lailerd and Orawan Wongmekiat

Biomolecules 2022, 12(8), 1068; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12081068 - 02 Aug 2022

Cited by 2 | Viewed by 2707

Abstract

Diabetic nephropathy is currently the leading cause of end-stage renal disease (ESRD) in type 2 diabetes. Studies have suggested that supplementation with some fatty acids might reduce the risk and delay the progression to ESRD in patient with chronic kidney disease. Crocodile oil [...] Read more.

Diabetic nephropathy is currently the leading cause of end-stage renal disease (ESRD) in type 2 diabetes. Studies have suggested that supplementation with some fatty acids might reduce the risk and delay the progression to ESRD in patient with chronic kidney disease. Crocodile oil (CO) contains a variety of fatty acids, especially omega-3, -6 and -9, that have been reported to be beneficial to human health. This study examined the impact of long-term CO supplementation on the development of diabetic nephropathy in spontaneously diabetic Torii (SDT) rats. After diabetic verification, SDT rats were assigned to receive vehicle or CO at 500 and 1000 mg/kg BW, respectively, by oral gavage. Age-matched nondiabetic Sprague–Dawley rats were given vehicle or high-dose CO. After 28 weeks of intervention, CO failed to improve hyperglycemia and pancreatic histopathological changes in SDT rats. Unexpectedly, CO dose-dependently exacerbated the impairment of kidney and mitochondrial functions caused by diabetes. CO also disturbed the expressions of proteins involved in mitochondrial biogenesis, dynamics, and mitophagy. However, no significant alterations were observed in nondiabetic rats receiving high-dose CO. The findings reveal that CO has deleterious effects that aggravate diabetic kidney injury via disrupting mitochondrial homeostasis, possibly due to its improper omega-6: omega-3 ratio. Full article

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

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Review

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15 pages, 1038 KiB

Open AccessReview

Inspiring Tactics with the Improvement of Mitophagy and Redox Balance for the Development of Innovative Treatment against Polycystic Kidney Disease

by Moeka Nakashima, Naoko Suga, Yuka Ikeda, Sayuri Yoshikawa and Satoru Matsuda

Biomolecules 2024, 14(2), 207; https://0-doi-org.brum.beds.ac.uk/10.3390/biom14020207 - 09 Feb 2024

Viewed by 1188

Abstract

Polycystic kidney disease (PKD) is the most common genetic form of chronic kidney disease (CKD), and it involves the development of multiple kidney cysts. Not enough medical breakthroughs have been made against PKD, a condition which features regional hypoxia and activation of the [...] Read more.

Polycystic kidney disease (PKD) is the most common genetic form of chronic kidney disease (CKD), and it involves the development of multiple kidney cysts. Not enough medical breakthroughs have been made against PKD, a condition which features regional hypoxia and activation of the hypoxia-inducible factor (HIF) pathway. The following pathology of CKD can severely instigate kidney damage and/or renal failure. Significant evidence verifies an imperative role for mitophagy in normal kidney physiology and the pathology of CKD and/or PKD. Mitophagy serves as important component of mitochondrial quality control by removing impaired/dysfunctional mitochondria from the cell to warrant redox homeostasis and sustain cell viability. Interestingly, treatment with the peroxisome proliferator-activated receptor-α (PPAR-α) agonist could reduce the pathology of PDK and might improve the renal function of the disease via the modulation of mitophagy, as well as the condition of gut microbiome. Suitable modulation of mitophagy might be a favorable tactic for the prevention and/or treatment of kidney diseases such as PKD and CKD. Full article

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

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16 pages, 1251 KiB

Open AccessReview

Kidney Fibrosis and Oxidative Stress: From Molecular Pathways to New Pharmacological Opportunities

by Francesco Patera, Leonardo Gatticchi, Barbara Cellini, Davide Chiasserini and Gianpaolo Reboldi

Biomolecules 2024, 14(1), 137; https://0-doi-org.brum.beds.ac.uk/10.3390/biom14010137 - 22 Jan 2024

Cited by 1 | Viewed by 1404

Abstract

Kidney fibrosis, diffused into the interstitium, vessels, and glomerulus, is the main pathologic feature associated with loss of renal function and chronic kidney disease (CKD). Fibrosis may be triggered in kidney diseases by different genetic and molecular insults. However, several studies have shown [...] Read more.

Kidney fibrosis, diffused into the interstitium, vessels, and glomerulus, is the main pathologic feature associated with loss of renal function and chronic kidney disease (CKD). Fibrosis may be triggered in kidney diseases by different genetic and molecular insults. However, several studies have shown that fibrosis can be linked to oxidative stress and mitochondrial dysfunction in CKD. In this review, we will focus on three pathways that link oxidative stress and kidney fibrosis, namely: (i) hyperglycemia and mitochondrial energy imbalance, (ii) the mineralocorticoid signaling pathway, and (iii) the hypoxia-inducible factor (HIF) pathway. We selected these pathways because they are targeted by available medications capable of reducing kidney fibrosis, such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, non-steroidal mineralocorticoid receptor antagonists (MRAs), and HIF-1alpha-prolyl hydroxylase inhibitors. These drugs have shown a reduction in oxidative stress in the kidney and a reduced collagen deposition across different CKD subtypes. However, there is still a long and winding road to a clear understanding of the anti-fibrotic effects of these compounds in humans, due to the inherent practical and ethical difficulties in obtaining sequential kidney biopsies and the lack of specific fibrosis biomarkers measurable in easily accessible matrices like urine. In this narrative review, we will describe these three pathways, their interconnections, and their link to and activity in oxidative stress and kidney fibrosis. Full article

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

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25 pages, 925 KiB

Open AccessReview

Oxidative Stress and NRF2/KEAP1/ARE Pathway in Diabetic Kidney Disease (DKD): New Perspectives

by Daniela Maria Tanase, Evelina Maria Gosav, Madalina Ioana Anton, Mariana Floria, Petronela Nicoleta Seritean Isac, Loredana Liliana Hurjui, Claudia Cristina Tarniceriu, Claudia Florida Costea, Manuela Ciocoiu and Ciprian Rezus

Biomolecules 2022, 12(9), 1227; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12091227 - 02 Sep 2022

Cited by 44 | Viewed by 5065

Abstract

Diabetes mellitus (DM) is one of the most debilitating chronic diseases worldwide, with increased prevalence and incidence. In addition to its macrovascular damage, through its microvascular complications, such as Diabetic Kidney Disease (DKD), DM further compounds the quality of life of these patients. [...] Read more.

Diabetes mellitus (DM) is one of the most debilitating chronic diseases worldwide, with increased prevalence and incidence. In addition to its macrovascular damage, through its microvascular complications, such as Diabetic Kidney Disease (DKD), DM further compounds the quality of life of these patients. Considering DKD is the main cause of end-stage renal disease (ESRD) in developed countries, extensive research is currently investigating the matrix of DKD pathophysiology. Hyperglycemia, inflammation and oxidative stress (OS) are the main mechanisms behind this disease. By generating pro-inflammatory factors (e.g., IL-1,6,18, TNF-α, TGF-β, NF-κB, MCP-1, VCAM-1, ICAM-1) and the activation of diverse pathways (e.g., PKC, ROCK, AGE/RAGE, JAK-STAT), they promote a pro-oxidant state with impairment of the antioxidant system (NRF2/KEAP1/ARE pathway) and, finally, alterations in the renal filtration unit. Hitherto, a wide spectrum of pre-clinical and clinical studies shows the beneficial use of NRF2-inducing strategies, such as NRF2 activators (e.g., Bardoxolone methyl, Curcumin, Sulforaphane and their analogues), and other natural compounds with antioxidant properties in DKD treatment. However, limitations regarding the lack of larger clinical trials, solubility or delivery hamper their implementation for clinical use. Therefore, in this review, we will discuss DKD mechanisms, especially oxidative stress (OS) and NRF2/KEAP1/ARE involvement, while highlighting the potential of therapeutic approaches that target DKD via OS. Full article

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

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16 pages, 2056 KiB

Open AccessReview

The Nicotinamide/Streptozotocin Rodent Model of Type 2 Diabetes: Renal Pathophysiology and Redox Imbalance Features

by Liang-Jun Yan

Biomolecules 2022, 12(9), 1225; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12091225 - 02 Sep 2022

Cited by 12 | Viewed by 3549

Abstract

Diabetic nephropathy (DN) is a common complication of diabetes mellitus. While there has been a great advance in our understanding of the pathogenesis of DN, no effective managements of this chronic kidney disease are currently available. Therefore, continuing to elucidate the underlying biochemical [...] Read more.

Diabetic nephropathy (DN) is a common complication of diabetes mellitus. While there has been a great advance in our understanding of the pathogenesis of DN, no effective managements of this chronic kidney disease are currently available. Therefore, continuing to elucidate the underlying biochemical and molecular mechanisms of DN remains a constant need. In this regard, animal models of diabetes are indispensable tools. This review article highlights a widely used rodent model of non-obese type 2 diabetes induced by nicotinamide (NA) and streptozotocin (STZ). The mechanism underlying diabetes induction by combining the two chemicals involves blunting the toxic effect of STZ by NA so that only a percentage of β cells are destroyed and the remaining viable β cells can still respond to glucose stimulation. This NA-STZ animal model, as a platform for the testing of numerous antidiabetic and renoprotective materials, is also discussed. In comparison with other type 2 diabetic animal models, such as high-fat-diet/STZ models and genetically engineered rodent models, the NA-STZ model is non-obese and is less time-consuming and less expensive to create. Given that this unique model mimics certain pathological features of human DN, this model should continue to find its applications in the field of diabetes research. Full article

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

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