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Special Issue "Inflammation and Oxidative Stress in Kidney Disease"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 February 2020).

Special Issue Editor

Dr. Peter Hamar
E-Mail Website
Guest Editor
Institute of Pathophysiology, Semmelweis University, Budapest, Hungary
Interests: triple negative breast cancer (TNBC); modulated-electrohyperthermia (mEHT); ischemia induced acute kidney injury (IRI-AKI); non-coding RNAs (miRNA, siRNA, lncRNA); the role of fibrinogen in cell stress
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Special Issue Information

Dear colleagues,

Ischemia-reperfusion injury (IRI) is the leading cause of acute kidney injury (AKI). IRI can lead to renal transplantation as well as circulatory and septic shock. Moreover, it contributes to contrast-induced nephropathy and can lead to chronic kidney disease in the long term. The initial injury is aggravated by subsequent inflammation due to the deliberation of danger-associated molecular patterns (DAMP) and their recognition via toll-like receptors (TLRs). TLRs activate the inflammasome, the interferon (IFN) response, and the subsequent cytokine release initiates inflammation associated with oxidative stress. Cell death is primarily necrotic during ischemia, but tissue damage due to necroptosis or apoptosis occurs during reperfusion. Bacterial endotoxin (lipopolysaccharide)-induced immune-paralysis can provide protection from an otherwise lethal ischemic injury; however, the molecular mechanisms of this cross-tolerance are largely unknown.

An increasing body of evidence suggests that these processes are regulated or modulated by non-coding RNAs (lncRNA, miRNA) and thus can be therapeutically influenced by RNA-based therapies (mRNA, siRNA, ASO). The role of miR-21 has been already well established in disease states, but influencing miR-21 expression did not provide the expected clinical benefit. New miRs and lncRNAs are emerging as potential therapeutic tools to reduce reperfusion injury and chronic kidney disease.

Dr. Peter Hamar
Guest Editor

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Keywords

kidney;

ischemia-reperfusion injury;

endotoxin preconditioning;

inflammation;

oxidative stress;

non-coding RNAs (miRNA, lncRNA, siRNA);

aging;  

obesity related nephropathy;

fibrosis

 

 

Published Papers (11 papers)

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Research

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Open AccessArticle
Time-Dependent miRNA Profile during Septic Acute Kidney Injury in Mice
Int. J. Mol. Sci. 2020, 21(15), 5316; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155316 - 27 Jul 2020
Cited by 2 | Viewed by 516
Abstract
(1) Background: Lipopolysaccharide (LPS)-induced systemic inflammation is associated with septic acute kidney injury (AKI). We investigated the time-dependent miRNA expression changes in the kidney caused by LPS. (2) Methods: Male outbred NMRI mice were injected with LPS and sacrificed at 1.5 and 6 [...] Read more.
(1) Background: Lipopolysaccharide (LPS)-induced systemic inflammation is associated with septic acute kidney injury (AKI). We investigated the time-dependent miRNA expression changes in the kidney caused by LPS. (2) Methods: Male outbred NMRI mice were injected with LPS and sacrificed at 1.5 and 6 h (40 mg/kg i.p., early phase, EP) or at 24 and 48 h (10 mg/kg i.p., late phase, LP). The miRNA profile was established using miRCURY LNA™ microarray and confirmed with qPCR. Total renal proteome was analyzed by LC-MS/MS (ProteomeXchange: PXD014664). (3) Results: Septic AKI was confirmed by increases in plasma urea concentration and in renal TNF-α and IL-6 mRNA expression. Most miRNAs were altered at 6 and 24 h and declined by 48 h. In EP miR-762 was newly identified and validated and was the most elevated miRNA. The predicted target of miR-762, Ras related GTPase 1B (Sar1b) was downregulated. In LP miR-21a-5p was the most influenced miRNA followed by miR-451a, miR-144-3p, and miR-146a-5p. Among the potential protein targets of the most influenced miRNAs, only aquaporin-1, a target of miR-144-3p was downregulated at 24 h. (4) Conclusion: Besides already known miRNAs, septic AKI upregulated miR-762, which may regulate GTP signaling, and miR-144-3p and downregulated its target, aquaporin-1. Full article
(This article belongs to the Special Issue Inflammation and Oxidative Stress in Kidney Disease)
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Open AccessArticle
Post-Ischemic Renal Fibrosis Progression Is Halted by Delayed Contralateral Nephrectomy: The Involvement of Macrophage Activation
Int. J. Mol. Sci. 2020, 21(11), 3825; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113825 - 28 May 2020
Viewed by 633
Abstract
(1) Background: Successful treatment of acute kidney injury (AKI)-induced chronic kidney disease (CKD) is unresolved. We aimed to characterize the time-course of changes after contralateral nephrectomy (Nx) in a model of unilateral ischemic AKI-induced CKD with good translational utility. (2) Methods: Severe (30 [...] Read more.
(1) Background: Successful treatment of acute kidney injury (AKI)-induced chronic kidney disease (CKD) is unresolved. We aimed to characterize the time-course of changes after contralateral nephrectomy (Nx) in a model of unilateral ischemic AKI-induced CKD with good translational utility. (2) Methods: Severe (30 min) left renal ischemia-reperfusion injury (IRI) or sham operation (S) was performed in male Naval Medical Research Institute (NMRI) mice followed by Nx or S one week later. Expression of proinflammatory, oxidative stress, injury and fibrotic markers was evaluated by RT-qPCR. (3) Results: Upon Nx, the injured kidney hardly functioned for three days, but it gradually regained function until day 14 to 21, as demonstrated by the plasma urea. Functional recovery led to a drastic reduction in inflammatory infiltration by macrophages and by decreases in macrophage chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-α) mRNA and most injury markers. However, without Nx, a marked upregulation of proinflammatory (TNF-α, IL-6, MCP-1 and complement-3 (C3)); oxidative stress (nuclear factor erythroid 2-related factor 2, NRF2) and fibrosis (collagen-1a1 (Col1a1) and fibronectin-1 (FN1)) genes perpetuated, and the injured kidney became completely fibrotic. Contralateral Nx delayed the development of renal failure up to 20 weeks. (4) Conclusion: Our results suggest that macrophage activation is involved in postischemic renal fibrosis, and it is drastically suppressed by contralateral nephrectomy ameliorating progression. Full article
(This article belongs to the Special Issue Inflammation and Oxidative Stress in Kidney Disease)
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Open AccessArticle
ECM Characterization Reveals a Massive Activation of Acute Phase Response during FSGS
Int. J. Mol. Sci. 2020, 21(6), 2095; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062095 - 18 Mar 2020
Cited by 1 | Viewed by 1009
Abstract
The glomerular basement membrane (GBM) and extra-cellular matrix (ECM) are essential to maintain a functional interaction between the glomerular podocytes and the fenestrated endothelial cells in the formation of the slit diaphragm for the filtration of blood. Dysregulation of ECM homeostasis can cause [...] Read more.
The glomerular basement membrane (GBM) and extra-cellular matrix (ECM) are essential to maintain a functional interaction between the glomerular podocytes and the fenestrated endothelial cells in the formation of the slit diaphragm for the filtration of blood. Dysregulation of ECM homeostasis can cause Focal segmental glomerulosclerosis (FSGS). Despite this central role, alterations in ECM composition during FSGS have not been analyzed in detail yet. Here, we characterized the ECM proteome changes in miR-193a-overexpressing mice, which suffer from FSGS due to suppression of Wilms’ tumor 1 (WT1). By mass spectrometry we identified a massive activation of the acute phase response, especially the complement and fibrinogen pathways. Several protease inhibitors (ITIH1, SERPINA1, SERPINA3) were also strongly increased. Complementary analysis of RNA expression data from both miR-193a mice and human FSGS patients identified additional candidate genes also mainly involved in the acute phase response. In total, we identified more than 60 dysregulated, ECM-associated genes with potential relevance for FSGS progression. Our comprehensive analysis of a murine FSGS model and translational comparison with human data offers novel targets for FSGS therapy. Full article
(This article belongs to the Special Issue Inflammation and Oxidative Stress in Kidney Disease)
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Open AccessArticle
Underlying Histopathology Determines Response to Oxidative Stress in Cultured Human Primary Proximal Tubular Epithelial Cells
Int. J. Mol. Sci. 2020, 21(2), 560; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21020560 - 15 Jan 2020
Cited by 1 | Viewed by 809
Abstract
Proximal tubular epithelial cells (PTEC) are key players in the progression of kidney diseases. PTEC studies to date have primarily used mouse models and transformed human PTEC lines. However, the translatability of these models to human kidney disease has been questioned. In this [...] Read more.
Proximal tubular epithelial cells (PTEC) are key players in the progression of kidney diseases. PTEC studies to date have primarily used mouse models and transformed human PTEC lines. However, the translatability of these models to human kidney disease has been questioned. In this study, we investigated the phenotypic and functional response of human primary PTEC to oxidative stress, an established driver of kidney disease. Furthermore, we examined the functional contribution of the underlying histopathology of the cortical tissue used to generate our PTEC. We demonstrated that human primary PTEC from both histologically ‘normal’ and ‘diseased’ cortical tissue responded to H2O2-induced oxidative stress with significantly elevated mitochondrial superoxide levels, DNA damage, and significantly decreased proliferation. The functional response of ‘normal’ PTEC to oxidative stress mirrored the reported pathogenesis of human kidney disease, with significantly attenuated mitochondrial function and increased cell death. In contrast, ‘diseased’ PTEC were functionally resistant to oxidative stress, with maintenance of mitochondrial function and cell viability. This selective survival of ‘diseased’ PTEC under oxidizing conditions is reminiscent of the in vivo persistence of maladaptive PTEC following kidney injury. We are now exploring the impact that these differential PTEC responses have in the therapeutic targeting of oxidative stress pathways. Full article
(This article belongs to the Special Issue Inflammation and Oxidative Stress in Kidney Disease)
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Open AccessArticle
Sirtuin 3 Activation by Honokiol Decreases Unilateral Ureteral Obstruction-Induced Renal Inflammation and Fibrosis via Regulation of Mitochondrial Dynamics and the Renal NF-κB-TGF-β1/Smad Signaling Pathway
Int. J. Mol. Sci. 2020, 21(2), 402; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21020402 - 08 Jan 2020
Cited by 6 | Viewed by 1152
Abstract
Renal fibrosis is a common feature of all progressive chronic kidney diseases. Sirtuin 3 (SIRT3) is one of the mitochondrial sirtuins, and plays a role in the regulation of mitochondrial biogenesis, oxidative stress, fatty acid metabolism, and aging. Recently, honokiol (HKL), as a [...] Read more.
Renal fibrosis is a common feature of all progressive chronic kidney diseases. Sirtuin 3 (SIRT3) is one of the mitochondrial sirtuins, and plays a role in the regulation of mitochondrial biogenesis, oxidative stress, fatty acid metabolism, and aging. Recently, honokiol (HKL), as a pharmaceutical SIRT3 activator, has been observed to have a protective effect against pressure overload-induced cardiac hypertrophy by increasing SIRT3 activity. In this study, we investigated whether HKL, as a SIRT3 activator, also has protective effects against unilateral ureteral obstruction (UUO)-induced renal tubulointerstitial fibrosis through SIRT3-dependent regulation of mitochondrial dynamics and the nuclear factor-κB (NF-κB)/transforming growth factor-β1 (TGF-β1)/Smad signaling pathway. We found that HKL decreased the UUO-induced increase in tubular injury and extracellular matrix (ECM) deposition in mice. HKL also decreased myofibroblast activation and proliferation in UUO kidneys and NRK-49F cells. Finally, we showed that HKL treatment decreased UUO-induced mitochondrial fission and promoted mitochondrial fusion through SIRT3-dependent effects. In conclusion, activation of SIRT3 via HKL treatment might have beneficial effects on UUO-induced renal fibrosis through SIRT3-dependent regulation of mitochondrial dynamics and the NF-κB/TGF-β1/Smad signaling pathway. Full article
(This article belongs to the Special Issue Inflammation and Oxidative Stress in Kidney Disease)
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Open AccessArticle
The Acute Phase Response Is a Prominent Renal Proteome Change in Sepsis in Mice
Int. J. Mol. Sci. 2020, 21(1), 200; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010200 - 27 Dec 2019
Cited by 5 | Viewed by 1011
Abstract
(1) Background: Sepsis-induced acute kidney injury (AKI) is the most common form of acute kidney injury (AKI). We studied the temporal profile of the sepsis-induced renal proteome changes. (2) Methods: Male mice were injected intraperitoneally with bacterial lipopolysaccharide (LPS) or saline (control). Renal [...] Read more.
(1) Background: Sepsis-induced acute kidney injury (AKI) is the most common form of acute kidney injury (AKI). We studied the temporal profile of the sepsis-induced renal proteome changes. (2) Methods: Male mice were injected intraperitoneally with bacterial lipopolysaccharide (LPS) or saline (control). Renal proteome was studied by LC-MS/MS (ProteomeXchange: PXD014664) at the early phase (EP, 1.5 and 6 h after 40 mg/kg LPS) and the late phase (LP, 24 and 48 h after 10 mg/kg LPS) of LPS-induced AKI. Renal mRNA expression of acute phase proteins (APP) was assessed by qPCR. (3) Results: Renal proteome change was milder in EP vs. LP. APPs dominated the proteome in LP (proteins upregulated at least 4-fold (APPs/all): EP, 1.5 h: 0/10, 6 h: 1/10; LP, 24 h: 22/47, 48 h: 17/44). Lipocalin-2, complement C3, fibrinogen, haptoglobin and hemopexin were the most upregulated APPs. Renal mRNA expression preceded the APP changes with peak effects at 24 h, and indicated renal production of the majority of APPs. (4) Conclusions: Gene expression analysis revealed local production of APPs that commenced a few hours post injection and peaked at 24 h. This is the first demonstration of a massive, complex and coordinated acute phase response of the kidney involving several proteins not identified previously. Full article
(This article belongs to the Special Issue Inflammation and Oxidative Stress in Kidney Disease)
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Open AccessArticle
Glomerular Collagen Deposition and Lipocalin-2 Expression Are Early Signs of Renal Injury in Prediabetic Obese Rats
Int. J. Mol. Sci. 2019, 20(17), 4266; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20174266 - 30 Aug 2019
Cited by 2 | Viewed by 1313
Abstract
Feeding rats with high-fat diet (HFD) with a single streptozotocin (STZ) injection induced obesity, slightly elevated fasting blood glucose and impaired glucose and insulin tolerance, and caused cardiac hypertrophy and mild diastolic dysfunction as published before by Koncsos et al. in 2016. Here [...] Read more.
Feeding rats with high-fat diet (HFD) with a single streptozotocin (STZ) injection induced obesity, slightly elevated fasting blood glucose and impaired glucose and insulin tolerance, and caused cardiac hypertrophy and mild diastolic dysfunction as published before by Koncsos et al. in 2016. Here we aimed to explore the renal consequences in the same groups of rats. Male Long-Evans rats were fed normal chow (CON; n = 9) or HFD containing 40% lard and were administered STZ at 20 mg/kg (i.p.) at week four (prediabetic rats, PRED, n = 9). At week 21 blood and urine samples were taken and kidney and liver samples were collected for histology, immunohistochemistry and for analysis of gene expression. HFD and STZ increased body weight and visceral adiposity and plasma leptin concentration. Despite hyperleptinemia, plasma C-reactive protein concentration decreased in PRED rats. Immunohistochemistry revealed elevated collagen IV protein expression in the glomeruli, and Lcn2 mRNA expression increased, while Il-1β mRNA expression decreased in both the renal cortex and medulla in PRED vs. CON rats. Kidney histology, urinary protein excretion, plasma creatinine, glomerular Feret diameter, desmin protein expression, and cortical and medullary mRNA expression of TGF-β1, Nrf2, and PPARγ were similar in CON and PRED rats. Reduced AMPKα phosphorylation of the autophagy regulator Akt was the first sign of liver damage, while plasma lipid and liver enzyme concentrations were similar. In conclusion, glomerular collagen deposition and increased lipocalin-2 expression were the early signs of kidney injury, while most biomarkers of inflammation, oxidative stress and fibrosis were negative in the kidneys of obese, prediabetic rats with mild heart and liver injury. Full article
(This article belongs to the Special Issue Inflammation and Oxidative Stress in Kidney Disease)
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Open AccessArticle
The Xanthine Oxidase Inhibitor Febuxostat Suppresses the Progression of IgA Nephropathy, Possibly via Its Anti-Inflammatory and Anti-Fibrotic Effects in the gddY Mouse Model
Int. J. Mol. Sci. 2018, 19(12), 3967; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19123967 - 10 Dec 2018
Cited by 5 | Viewed by 2469
Abstract
Recent clinical studies have demonstrated the protective effect of xanthine oxidase (XO) inhibitors against chronic kidney diseases, although the underlying molecular mechanisms remain unclear. However, to date, neither clinical nor basic research has been carried out to elucidate the efficacy of XO inhibitor [...] Read more.
Recent clinical studies have demonstrated the protective effect of xanthine oxidase (XO) inhibitors against chronic kidney diseases, although the underlying molecular mechanisms remain unclear. However, to date, neither clinical nor basic research has been carried out to elucidate the efficacy of XO inhibitor administration for IgA nephropathy. We thus investigated whether febuxostat, an XO inhibitor, exerts a protective effect against the development of IgA nephropathy, using gddY mice as an IgA nephropathy rodent model. Eight-week-old gddY mice were provided drinking water with (15 μg/mL) or without febuxostat for nine weeks and then subjected to experimentation. Elevated serum creatinine and degrees of glomerular sclerosis and fibrosis, judged by microscopic observations, were significantly milder in the febuxostat-treated than in the untreated gddY mice, while body weights and serum IgA concentrations did not differ between the two groups. In addition, elevated mRNA levels of inflammatory cytokines such as TNFα, MCP-1, IL-1β, and IL-6, collagen isoforms and chemokines in the gddY mouse kidneys were clearly normalized by the administration of febuxostat. These data suggest a protective effect of XO inhibitors against the development of IgA nephropathy, possibly via suppression of inflammation and its resultant fibrotic changes, without affecting the serum IgA concentration. Full article
(This article belongs to the Special Issue Inflammation and Oxidative Stress in Kidney Disease)
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Review

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Open AccessReview
The Neuropeptide Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Is Protective in Inflammation and Oxidative Stress-Induced Damage in the Kidney
Int. J. Mol. Sci. 2019, 20(19), 4944; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20194944 - 07 Oct 2019
Cited by 10 | Viewed by 1071
Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide with a widespread distribution throughout the entire body including the urinary system. PACAP exerts protective actions in different injury models related to several organ systems. Its protective effect is mainly based on its antiapoptotic, [...] Read more.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide with a widespread distribution throughout the entire body including the urinary system. PACAP exerts protective actions in different injury models related to several organ systems. Its protective effect is mainly based on its antiapoptotic, anti-inflammatory and antioxidant effects. The present review aims to summarize the effects of PACAP in pathologies associated with inflammation and oxidative stress-induced damage in the kidney. Both in vitro and in vivo data are available proving its protective actions against oxidative stress, hypoxia, renal ischemia/reperfusion, diabetic nephropathy, myeloma kidney injury, amyloidosis and different types of drug-induced nephropathies. Data showing the nephroprotection by PACAP emphasize the potential of PACAP’s therapeutic use in various renal pathologies. Full article
(This article belongs to the Special Issue Inflammation and Oxidative Stress in Kidney Disease)
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Open AccessReview
Molecular Interactions Between Reactive Oxygen Species and Autophagy in Kidney Disease
Int. J. Mol. Sci. 2019, 20(15), 3791; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20153791 - 03 Aug 2019
Cited by 27 | Viewed by 2671
Abstract
Reactive oxygen species (ROS) are highly reactive signaling molecules that maintain redox homeostasis in mammalian cells. Dysregulation of redox homeostasis under pathological conditions results in excessive generation of ROS, culminating in oxidative stress and the associated oxidative damage of cellular components. ROS and [...] Read more.
Reactive oxygen species (ROS) are highly reactive signaling molecules that maintain redox homeostasis in mammalian cells. Dysregulation of redox homeostasis under pathological conditions results in excessive generation of ROS, culminating in oxidative stress and the associated oxidative damage of cellular components. ROS and oxidative stress play a vital role in the pathogenesis of acute kidney injury and chronic kidney disease, and it is well documented that increased oxidative stress in patients enhances the progression of renal diseases. Oxidative stress activates autophagy, which facilitates cellular adaptation and diminishes oxidative damage by degrading and recycling intracellular oxidized and damaged macromolecules and dysfunctional organelles. In this review, we report the current understanding of the molecular regulation of autophagy in response to oxidative stress in general and in the pathogenesis of kidney diseases. We summarize how the molecular interactions between ROS and autophagy involve ROS-mediated activation of autophagy and autophagy-mediated reduction of oxidative stress. In particular, we describe how ROS impact various signaling pathways of autophagy, including mTORC1-ULK1, AMPK-mTORC1-ULK1, and Keap1-Nrf2-p62, as well as selective autophagy including mitophagy and pexophagy. Precise elucidation of the molecular mechanisms of interactions between ROS and autophagy in the pathogenesis of renal diseases may identify novel targets for development of drugs for preventing renal injury. Full article
(This article belongs to the Special Issue Inflammation and Oxidative Stress in Kidney Disease)
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Open AccessReview
Oxidative Stress in the Pathogenesis and Evolution of Chronic Kidney Disease: Untangling Ariadne’s Thread
Int. J. Mol. Sci. 2019, 20(15), 3711; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20153711 - 29 Jul 2019
Cited by 39 | Viewed by 2130
Abstract
Amplification of oxidative stress is present since the early stages of chronic kidney disease (CKD), holding a key position in the pathogenesis of renal failure. Induction of renal pro-oxidant enzymes with excess generation of reactive oxygen species (ROS) and accumulation of dityrosine-containing protein [...] Read more.
Amplification of oxidative stress is present since the early stages of chronic kidney disease (CKD), holding a key position in the pathogenesis of renal failure. Induction of renal pro-oxidant enzymes with excess generation of reactive oxygen species (ROS) and accumulation of dityrosine-containing protein products produced during oxidative stress (advanced oxidation protein products—AOPPs) have been directly linked to podocyte damage, proteinuria, and the development of focal segmental glomerulosclerosis (FSGS) as well as tubulointerstitial fibrosis. Vascular oxidative stress is considered to play a critical role in CKD progression, and ROS are potential mediators of the impaired myogenic responses of afferent renal arterioles in CKD and impaired renal autoregulation. Both oxidative stress and inflammation are CKD hallmarks. Oxidative stress promotes inflammation via formation of proinflammatory oxidized lipids or AOPPs, whereas activation of nuclear factor κB transcription factor in the pro-oxidant milieu promotes the expression of proinflammatory cytokines and recruitment of proinflammatory cells. Accumulating evidence implicates oxidative stress in various clinical models of CKD, including diabetic nephropathy, IgA nephropathy, polycystic kidney disease as well as the cardiorenal syndrome. The scope of this review is to tackle the issue of oxidative stress in CKD in a holistic manner so as to provide a future framework for potential interventions. Full article
(This article belongs to the Special Issue Inflammation and Oxidative Stress in Kidney Disease)
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