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Cellular-Redox-Related Stress Responses in Renal Disease and Their Related Complications

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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 (31 May 2022) | Viewed by 19236

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Dr. Raul Rodrigues-Diez

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1. Molecular and Cellular Biology in Renal and Vascular Pathology. IIS-Fundación Jiménez Díaz-Universidad Autónoma Madrid, Madrid, Spain
2. Red de Investigación Renal (REDINREN) Spain, Madrid, Spain
Interests: renal diseases; cardiovascular diseases; basic research; inflammation; fibrosis
Special Issues, Collections and Topics in MDPI journals

Dr. Beatriz Suárez-Álvarez

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Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
Interests: nephrology; immunology; epigenetic mechanisms; tolerance

Dr. Lucas Matias Opazo-Ríos

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Renal, Vascular and Diabetes Research Laboratory, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz (IIS-FJD).
Interests: diabetic nephropathy; non-alcoholic fatty liver disease; anti-hyperglicemic therapies (SGLT2i, GLP-1 RA, among others)

Special Issue Information

Dear Colleagues,

Cells continuously experience several classes of stress, which contributes to cellular damage. To resolve this situation, cells trigger specific transcriptional programs and cellular stress responses to restore cellular homeostasis. Some of these are hypoxic stress response, unfolded protein response in mitochondria and endoplasmic reticulum, oxidative stress response, heat shock response, or autophagy, among others. When these stimuli or stressors are extraordinarily strong or persistent on time, cells undergo irreversible damage or cell death, contributing to enhancing susceptibility to disease or aggravating it. Once we know the mechanisms involved in the intracellular responses to stress, it is relevant to elucidate their regulation, the pathophysiological consequences in the renal context, and the signals triggered by these responses to communicate damage to other cells and tissues such as the cardiovascular system. Striking a balance between the molecular mechanisms aimed at restoring homeostasis and those which contribute to maladaptation and disease is key to slowing the progression of disease.

Dr. Raul Rodrigues-Diez
Dr. Beatriz Suárez-Álvarez
Dr. Lucas Matias Opazo-Ríos
Guest Editors

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Keywords

Cellular stressors
Hypoxia
ER stress
Oxidative stress
Cellular homeostasis
Adaptative responses

Published Papers (7 papers)

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Research

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17 pages, 7335 KiB

Open AccessArticle

Renal Ischemia/Reperfusion Mitigation via Geraniol: The Role of Nrf-2/HO-1/NQO-1 and TLR2,4/MYD88/NFκB Pathway

by Maged E. Mohamed, Mohammad A. Elmorsy and Nancy S. Younis

Antioxidants 2022, 11(8), 1568; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11081568 - 13 Aug 2022

Cited by 4 | Viewed by 1598

Abstract

Background: Renal ischemia/reperfusion injury is a clinically recurrent event during kidney transplantation. Geraniol is a natural monoterpene essential oil component. This study aimed to inspect geraniol’s reno-protective actions against renal I/R injury with further analysis of embedded mechanisms of action through scrutinizing the Nrf-2/HO-1/NQO-1 and TLR2,4/MYD88/NFκB signaling pathways. Methods: Wistar male rats were randomized into five groups: Sham, Sham + geraniol, Renal I/R, and two Renal I/R + geraniol groups representing two doses of geraniol (100 and 200 mg/kg) for 14 days before the renal I/R. Renal I/R was surgically induced by occluding both left and right renal pedicles for 45 min, followed by reperfusion for 24 h. A docking study was performed to anticipate the expected affinity of geraniol towards three protein targets: hTLR4/MD2, hTLR2, and hNrf2/Keap1. Results: Renal I/R rats experienced severely compromised renal functions, histological alteration, oxidative stress status, escalated Nrf-2/HO-1/NQO-1, and amplified TLR2,4/MYD88/NFκB. Geraniol administration ameliorated renal function, alleviated histological changes, and enhanced Nrf-2/HO-1/NQO-1 with a subsequent intensification of antioxidant enzyme activities. Geraniol declined TLR2,4/MYD88/NFκB with subsequent TNF-α, IFN-γ, MCP-1 drop, Bax, caspase-3, and caspase-9 reduction IL-10 and Bcl-2 augmentation. Geraniol exhibited good fitting in the binding sites of the three in silico examined targets. Conclusions: Geraniol might protect against renal I/R via the inhibition of the TLR2,4/MYD88/NFκB pathway, mediating anti-inflammation and activation of the Nrf2 pathway, intervening in antioxidative activities. Full article

(This article belongs to the Special Issue Cellular-Redox-Related Stress Responses in Renal Disease and Their Related Complications)

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16 pages, 3131 KiB

Open AccessArticle

Demethylation of H3K9 and H3K27 Contributes to the Tubular Renal Damage Triggered by Endoplasmic Reticulum Stress

by Paula Diaz-Bulnes, Maria Laura Saiz, Viviana Corte-Iglesias, Raúl R Rodrigues-Diez, Aida Bernardo Florez, Cristian Ruiz Bernet, Cristina Martin Martin, Marta Ruiz-Ortega, Beatriz Suarez-Alvarez and Carlos López-Larrea

Antioxidants 2022, 11(7), 1355; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11071355 - 12 Jul 2022

Cited by 8 | Viewed by 2075

Abstract

Loss of protein homeostasis (proteostasis) in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR), restoring correct protein folding. Sustained ER stress exacerbates activation of the major UPR branches (IRE1α/XBP1, PERK/ATF4, ATF6), inducing expression of numerous genes involved in inflammation, cell death, autophagy, and oxidative stress. We investigated whether epigenetic dynamics mediated by histone H3K9 and H3K27 methylation might help to reduce or inhibit the exacerbated and maladaptive UPR triggered in tubular epithelial cells. Epigenetic treatments, specific silencing, and chromatin immunoprecipitation assays were performed in human proximal tubular cells subjected to ER stress. Pharmacological blockage of KDM4C and JMJD3 histone demethylases with SD-70 and GSKJ4, respectively, enhanced trimethylation of H3K9 and H3K27 in the ATF4 and XBP1 genes, inhibiting their expression and that of downstream genes. Conversely, specific G9a and EZH2 knockdown revealed increases in ATF4 and XBP1 expression. This is a consequence of the reduced recruitment of G9a and EZH2 histone methylases, diminished H3K9me3 and H3K27me3 levels, and enhanced histone acetylation at the ATF4 and XBP1 promoter region. G9a and EZH2 cooperate to maintain the repressive chromatin structure in both UPR-induced genes, ATF4 and XBP1. Therefore, preserving histone H3K9 and H3K27 methylation could ameliorate the ER stress, and consequently the oxidative stress and the triggered pathological processes that aggravate renal damage. Full article

(This article belongs to the Special Issue Cellular-Redox-Related Stress Responses in Renal Disease and Their Related Complications)

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15 pages, 8259 KiB

Open AccessArticle

The Protective Effect of Anethole against Renal Ischemia/Reperfusion: The Role of the TLR2,4/MYD88/NFκB Pathway

by Maged Elsayed Mohamed, Mahmoud Kandeel, Hany M. Abd El-Lateef, Hossam S. El-Beltagi and Nancy S. Younis

Antioxidants 2022, 11(3), 535; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11030535 - 11 Mar 2022

Cited by 15 | Viewed by 2603

Abstract

Background: Anethole is the principle essential oil component of anise and fennel. Renal ischemia/reperfusion (RIR) is one of the utmost imperative reasons for acute kidney injury and often associated with high mortality rate. The aim of this study is to investigate the protective effect of anethole on RIR status, exploring the involved mechanisms. Methods: RIR was accomplished by bilateral renal pedicle clamping for 45 min, after which the clamps were removed to achieve the reperfusion phase. Rats were randomized into five groups; Sham, Sham + anethole, RIR, and finally RIR + anethole (125 mg/kg or 250 mg/kg) groups. Animals were given anethole (in specified groups in doses) for 14 days before RIR. Results: RIR-experienced animals developed renal injury evidenced by diminished renal function and histopathological alteration. RIR induced severe oxidative, inflammatory, and apoptotic status within renal tissue. Pre-RIR management with anethole enhanced renal morphology and improved renal function. Anethole amplified GSH content and SOD, CAT, and GPx activities and lowered MDA. Anethole reduced gene and protein expression levels of HMGB1, TLR2, TLR4, MYD88, and NFκB. Anethole distinctly dropped TNF-α, IFN-γ, and MCP-1 levels, increased IL-10, and diminished caspase 3 and 9, reflecting its anti-inflammatory and anti-apoptotic actions. Conclusion: Anethole displayed anti-inflammatory, anti-oxidant, and anti-apoptotic actions against RIR-induced injury. Anethole exhibited renal protective actions, which could be through inhibiting the HMGB1/TLR2, 4/MYD88/NFκB pathway. These results could suggest anethole as a protective agent against RIR. Full article

(This article belongs to the Special Issue Cellular-Redox-Related Stress Responses in Renal Disease and Their Related Complications)

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16 pages, 4209 KiB

Open AccessArticle

CCN2 Aggravates the Immediate Oxidative Stress–DNA Damage Response following Renal Ischemia–Reperfusion Injury

by Floris A. Valentijn, Sebastiaan N. Knoppert, Georgios Pissas, Raúl R. Rodrigues-Diez, Laura Marquez-Exposito, Roel Broekhuizen, Michal Mokry, Lennart A. Kester, Lucas L. Falke, Roel Goldschmeding, Marta Ruiz-Ortega, Theodoros Eleftheriadis and Tri Q. Nguyen

Antioxidants 2021, 10(12), 2020; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10122020 - 20 Dec 2021

Cited by 19 | Viewed by 3221

Abstract

AKI, due to the fact of altered oxygen supply after kidney transplantation, is characterized by renal ischemia–reperfusion injury (IRI). Recent data suggest that AKI to CKD progression may be driven by cellular senescence evolving from prolonged DNA damage response (DDR) following oxidative stress. Cellular communication factor 2 (CCN2, formerly called CTGF) is a major contributor to CKD development and was found to aggravate DNA damage and the subsequent DDR–cellular senescence–fibrosis sequence following renal IRI. We therefore investigated the impact of CCN2 inhibition on oxidative stress and DDR in vivo and in vitro. Four hours after reperfusion, full transcriptome RNA sequencing of mouse IRI kidneys revealed CCN2-dependent enrichment of several signaling pathways, reflecting a different immediate stress response to IRI. Furthermore, decreased staining for γH2AX and p-p53 indicated reduced DNA damage and DDR in tubular epithelial cells of CCN2 knockout (KO) mice. Three days after IRI, DNA damage and DDR were still reduced in CCN2 KO, and this was associated with reduced oxidative stress, marked by lower lipid peroxidation, protein nitrosylation, and kidney expression levels of Nrf2 target genes (i.e., HMOX1 and NQO1). Finally, silencing of CCN2 alleviated DDR and lipid peroxidation induced by anoxia-reoxygenation injury in cultured PTECs. Together, our observations suggest that CCN2 inhibition might mitigate AKI by reducing oxidative stress-induced DNA damage and the subsequent DDR. Thus, targeting CCN2 might help to limit post-IRI AKI. Full article

(This article belongs to the Special Issue Cellular-Redox-Related Stress Responses in Renal Disease and Their Related Complications)

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17 pages, 3089 KiB

Open AccessArticle

Nephroprotective Effects of Synthetic Flavonoid Hidrosmin in Experimental Diabetic Nephropathy

by Luna Jiménez-Castilla, Gema Marín-Royo, Macarena Orejudo, Lucas Opazo-Ríos, Teresa Caro-Ordieres, Inés Artaiz, Tatiana Suárez-Cortés, Arturo Zazpe, Gonzalo Hernández, Carmen Gómez-Guerrero and Jesús Egido

Antioxidants 2021, 10(12), 1920; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10121920 - 29 Nov 2021

Cited by 5 | Viewed by 2236

Abstract

Diabetes mellitus (DM) is a high-impact disease commonly characterized by hyperglycemia, inflammation, and oxidative stress. Diabetic nephropathy (DN) is a common diabetic microvascular complication and the leading cause of chronic kidney disease worldwide. This study investigates the protective effects of the synthetic flavonoid hidrosmin (5-O-(beta-hydroxyethyl) diosmin) in experimental DN induced by streptozotocin injection in apolipoprotein E deficient mice. Oral administration of hidrosmin (300 mg/kg/day, n = 11) to diabetic mice for 7 weeks markedly reduced albuminuria (albumin-to-creatinine ratio: 47 ± 11% vs. control) and ameliorated renal pathological damage and expression of kidney injury markers. Kidneys of hidrosmin-treated mice exhibited lower content of macrophages and T cells, reduced expression of cytokines and chemokines, and attenuated inflammatory signaling pathways. Hidrosmin treatment improved the redox balance by reducing prooxidant enzymes and enhancing antioxidant genes, and also decreased senescence markers in diabetic kidneys. In vitro, hidrosmin dose-dependently reduced the expression of inflammatory and oxidative genes in tubuloepithelial cells exposed to either high-glucose or cytokines, with no evidence of cytotoxicity at effective concentrations. In conclusion, the synthetic flavonoid hidrosmin exerts a beneficial effect against DN by reducing inflammation, oxidative stress, and senescence pathways. Hidrosmin could have a potential role as a coadjutant therapy for the chronic complications of DM. Full article

(This article belongs to the Special Issue Cellular-Redox-Related Stress Responses in Renal Disease and Their Related Complications)

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17 pages, 35992 KiB

Open AccessArticle

The Protective Effects of α-Mangostin Attenuate Sodium Iodate-Induced Cytotoxicity and Oxidative Injury via Mediating SIRT-3 Inactivation via the PI3K/AKT/PGC-1α Pathway

by Chen-Ju Chuang, Meilin Wang, Jui-Hsuan Yeh, Tzu-Chun Chen, Shang-Chun Tsou, Yi-Ju Lee, Yuan-Yen Chang and Hui-Wen Lin

Antioxidants 2021, 10(12), 1870; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10121870 - 24 Nov 2021

Cited by 9 | Viewed by 2173

Abstract

It is well known that age-related macular degeneration (AMD) is an irreversible neurodegenerative disease that can cause blindness in the elderly. Oxidative stress-induced retinal pigment epithelial (RPE) cell damage is a part of the pathogenesis of AMD. In this study, we evaluated the [...] Read more.

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M) significantly increased cell viability and reduced apoptosis from NaIO₃-induced oxidative stress in a concentration-dependent manner, which was achieved by the inhibition of Bax, cleaved PARP-1, cleaved caspase-3 protein expression, and enhancement of Bcl-2 protein. Furthermore, pre-incubation of ARPE-19 cells with

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-MG markedly inhibited the intracellular ROS and extracellular H₂O₂ generation via blocking of the abnormal enzyme activities of superoxide dismutase (SOD), the downregulated levels of catalase (CAT), and the endogenous antioxidant, glutathione (GSH), which were regulated by decreasing PI3K-AKT-PGC-1

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-MG effectively protects human ARPE-19 cells from NaIO₃-induced oxidative damage via antiapoptotic and antioxidant effects. Full article

(This article belongs to the Special Issue Cellular-Redox-Related Stress Responses in Renal Disease and Their Related Complications)

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21 pages, 2164 KiB

Open AccessReview

Tubular Mitochondrial Dysfunction, Oxidative Stress, and Progression of Chronic Kidney Disease

by Miguel Fontecha-Barriuso, Ana M. Lopez-Diaz, Juan Guerrero-Mauvecin, Veronica Miguel, Adrian M. Ramos, Maria D. Sanchez-Niño, Marta Ruiz-Ortega, Alberto Ortiz and Ana B. Sanz

Antioxidants 2022, 11(7), 1356; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11071356 - 12 Jul 2022

Cited by 30 | Viewed by 4053

Abstract

Acute kidney injury (AKI) and chronic kidney disease (CKD) are interconnected conditions, and CKD is projected to become the fifth leading global cause of death by 2040. New therapeutic approaches are needed. Mitochondrial dysfunction and oxidative stress have emerged as drivers of kidney injury in acute and chronic settings, promoting the AKI-to-CKD transition. In this work, we review the role of mitochondrial dysfunction and oxidative stress in AKI and CKD progression and discuss novel therapeutic approaches. Specifically, evidence for mitochondrial dysfunction in diverse models of AKI (nephrotoxicity, cytokine storm, and ischemia-reperfusion injury) and CKD (diabetic kidney disease, glomerulopathies) is discussed; the clinical implications of novel information on the key role of mitochondria-related transcriptional regulators peroxisome proliferator-activated receptor gamma coactivator 1-alpha, transcription factor EB (PGC-1α, TFEB), and carnitine palmitoyl-transferase 1A (CPT1A) in kidney disease are addressed; the current status of the clinical development of therapeutic approaches targeting mitochondria are updated; and barriers to the clinical development of mitochondria-targeted interventions are discussed, including the lack of clinical diagnostic tests that allow us to categorize the baseline renal mitochondrial dysfunction/mitochondrial oxidative stress and to monitor its response to therapeutic intervention. Finally, key milestones for further research are proposed. Full article

(This article belongs to the Special Issue Cellular-Redox-Related Stress Responses in Renal Disease and Their Related Complications)

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