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Keywords = membranous nephropathy

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17 pages, 10020 KiB  
Article
Membranous Nephropathy Target Antigens Display Podocyte-Specific and Non-Specific Expression in Healthy Kidneys
by Ying Dong, Hui Xu and Damu Tang
Genes 2025, 16(3), 241; https://doi.org/10.3390/genes16030241 - 20 Feb 2025
Viewed by 187
Abstract
Background/Objectives: Autoimmunity towards podocyte antigens causes membranous nephropathy (MN). Numerous MN target antigens (MNTAgs) have been reported, including PLA2R1, THSD7A, NTNG1, TGFBR3, HTRA1, NDNF, SEMA3B, FAT1, EXT1, CNTN1, NELL1, PCDH7, EXT2, PCSK6, and NCAM1, but their podocyte expression has not been thoroughly studied. [...] Read more.
Background/Objectives: Autoimmunity towards podocyte antigens causes membranous nephropathy (MN). Numerous MN target antigens (MNTAgs) have been reported, including PLA2R1, THSD7A, NTNG1, TGFBR3, HTRA1, NDNF, SEMA3B, FAT1, EXT1, CNTN1, NELL1, PCDH7, EXT2, PCSK6, and NCAM1, but their podocyte expression has not been thoroughly studied. Methods: We screened CZ CELLxGene single-cell RNA (scRNA) sequence datasets for those of adult, fetal, and mouse kidneys and analyzed the above MNTAgs’ expression. Results: In adult kidneys, most MNTAgs are present in podocytes, except PCSK6 and NCAM1. PLA2R1 is expressed significantly more than other MNTAgs in podocytes and is a major podocyte marker, consistent with PLA2R1 as the dominant MNTAg. Additionally, PLA2R1 is a top-upregulated gene in the podocytes of chronic kidney disease, acute kidney injury, and diabetic nephropathy, indicating its general role in causing podocyte injury. PLA2R1, NTNG1, HTRA1, and NDNF display podocyte-enriched expression along with elevated chromatin accessibility in podocytes, suggesting transcription initiation contributing to their preference expression in podocytes. In the fetal kidney, most MNTAgs are expressed in podocytes. While PLA2R1 is weakly present in podocytes, SEMA3B is abundantly expressed in immature and mature podocytes, supporting SEMA3B as a childhood MNTAg. In mouse kidneys, Thsd7a is the only MNTAg with a prominent level and podocyte-specific expression. Conclusions: Most MNTAgs are present in podocytes in adults and during renal development. In adults, PLA2R1 expression is highly enriched in podocytes and significantly upregulated in multiple kidney diseases accompanied by proteinuria. In mouse kidneys, Thsd7a is specifically expressed in podocytes at an elevated level. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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19 pages, 905 KiB  
Review
Membranous Nephropathy
by Claudio Ponticelli
J. Clin. Med. 2025, 14(3), 761; https://doi.org/10.3390/jcm14030761 - 24 Jan 2025
Viewed by 497
Abstract
Membranous nephropathy is a glomerular disease that may be caused by exogenous risk factors in genetically predisposed individuals (primary MN) or may be associated with other autoimmune diseases, drug exposure, or cytotoxic agents (secondary MN). Primary membranous nephropathy (PMN) is an autoimmune disease [...] Read more.
Membranous nephropathy is a glomerular disease that may be caused by exogenous risk factors in genetically predisposed individuals (primary MN) or may be associated with other autoimmune diseases, drug exposure, or cytotoxic agents (secondary MN). Primary membranous nephropathy (PMN) is an autoimmune disease in which antigens—mainly the phospholipase A2 receptor—are located in the podocytes and are targeted by circulating antibodies, leading to in situ formation of immune complexes that activate the complement system. Clinically, the disease is characterized by nephrotic syndrome (NS) and associated complications. The outcome of PMN can vary, but untreated patients with NS may progress to end-stage kidney disease (ESKD) in 35–40% of cases within 10 years. Treatment primarily aims to prevent NS complications and progression to ESKD. The most commonly used immunosuppressive drugs are rituximab, corticosteroids, cyclophosphamide, and calcineurin inhibitors. Most patients may experience an improvement of proteinuria, which can sometimes be followed by NS relapse. Fewer than 50% of patients with PMN achieve complete and stable remission. In addition to immunosuppressive therapy, antiproteinuric, anti-lipemic, and anticoagulant medicaments are often required. Full article
(This article belongs to the Special Issue Novelties in the Treatment of Glomerulonephritis)
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19 pages, 2810 KiB  
Article
Apple Polyphenol Mitigates Diabetic Nephropathy via Attenuating Renal Dysfunction with Antioxidation in Streptozotocin-Induced Diabetic Rats
by Chieh-Yu Wang, Dai-Lin Wu, Meng-Hsun Yu, Chih-Ying Wang, Hsin-Wen Liang and Huei-Jane Lee
Antioxidants 2025, 14(2), 130; https://doi.org/10.3390/antiox14020130 - 23 Jan 2025
Viewed by 639
Abstract
Diabetic nephropathy (DN) is a major cause of morbidity and mortality among patients with diabetes mellitus (DM). Studies have highlighted the critical role of reactive oxygen species (ROS) in the pathogenesis of DM and its complications. Apple polyphenol (AP) has demonstrated antioxidant properties [...] Read more.
Diabetic nephropathy (DN) is a major cause of morbidity and mortality among patients with diabetes mellitus (DM). Studies have highlighted the critical role of reactive oxygen species (ROS) in the pathogenesis of DM and its complications. Apple polyphenol (AP) has demonstrated antioxidant properties in various models. In this study, we investigated the effects of AP on DN in a rat model. Type 1 diabetes was induced in Sprague–Dawley rats via a single intraperitoneal injection of streptozotocin (65 mg/kg) (n = 8). Rats with blood glucose levels exceeding 250 mg/dL were treated with AP at dosages of 0.5%, 1%, or 2% (w/w) in drinking water for 10 weeks. AP administration significantly improved early-stage DN markers, including reductions in the blood urea nitrogen-to-creatinine ratio and the urinary albumin-to-creatinine ratio (ACR), in a dose-dependent manner. AP treatment also significantly lowered blood triglyceride levels and reduced lipid peroxidation in kidney tissues. Histological analysis revealed that AP attenuated renal hydropic change, reduced glomerular basement membrane thickening, and restored mitochondrial morphology in diabetic rats. Additionally, the upregulation of transforming growth factor-beta (TGF-β) observed in the diabetic kidney was attenuated by AP treatment. In H2O2-stimulated rat mesangial cells, AP reduced ROS levels, accompanied by a reduction in TGF-β expression. These findings suggest that AP exerts protective effects against DN by improving renal function and mitigating oxidative stress, indicating its potential as a nutraceutical supplement for slowing DN progression. Full article
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27 pages, 1493 KiB  
Review
Autophagy and Mitophagy in Diabetic Kidney Disease—A Literature Review
by Alina Mihaela Stanigut, Liliana Tuta, Camelia Pana, Luana Alexandrescu, Adrian Suceveanu, Nicoleta-Mirela Blebea and Ileana Adela Vacaroiu
Int. J. Mol. Sci. 2025, 26(2), 806; https://doi.org/10.3390/ijms26020806 - 18 Jan 2025
Viewed by 888
Abstract
Autophagy and mitophagy are critical cellular processes that maintain homeostasis by removing damaged organelles and promoting cellular survival under stress conditions. In the context of diabetic kidney disease, these mechanisms play essential roles in mitigating cellular damage. This review provides an in-depth analysis [...] Read more.
Autophagy and mitophagy are critical cellular processes that maintain homeostasis by removing damaged organelles and promoting cellular survival under stress conditions. In the context of diabetic kidney disease, these mechanisms play essential roles in mitigating cellular damage. This review provides an in-depth analysis of the recent literature on the relationship between autophagy, mitophagy, and diabetic kidney disease, highlighting the current state of knowledge, existing research gaps, and potential areas for future investigations. Diabetic nephropathy (DN) is traditionally defined as a specific form of kidney disease caused by long-standing diabetes, characterized by the classic histological lesions in the kidney, including mesangial expansion, glomerular basement membrane thickening, nodular glomerulosclerosis (Kimmelstiel–Wilson nodules), and podocyte injury. Clinical markers for DN are albuminuria and the gradual decline in glomerular filtration rate (GFR). Diabetic kidney disease (DKD) is a broader and more inclusive term, for all forms of chronic kidney disease (CKD) in individuals with diabetes, regardless of the underlying pathology. This includes patients who may have diabetes-associated kidney damage without the typical histological findings of diabetic nephropathy. It also accounts for patients with other coexisting kidney diseases (e.g., hypertensive nephrosclerosis, ischemic nephropathy, tubulointerstitial nephropathies), even in the absence of albuminuria, such as a reduction in GFR. Full article
(This article belongs to the Special Issue Molecular Mechanism of Diabetic Kidney Disease (2nd Edition))
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22 pages, 2994 KiB  
Review
Apolipoprotein-L Functions in Membrane Remodeling
by Etienne Pays
Cells 2024, 13(24), 2115; https://doi.org/10.3390/cells13242115 - 20 Dec 2024
Viewed by 1120
Abstract
The mammalian Apolipoprotein-L families (APOLs) contain several isoforms of membrane-interacting proteins, some of which are involved in the control of membrane dynamics (traffic, fission and fusion). Specifically, human APOL1 and APOL3 appear to control membrane remodeling linked to pathogen infection. Through its association [...] Read more.
The mammalian Apolipoprotein-L families (APOLs) contain several isoforms of membrane-interacting proteins, some of which are involved in the control of membrane dynamics (traffic, fission and fusion). Specifically, human APOL1 and APOL3 appear to control membrane remodeling linked to pathogen infection. Through its association with Non-Muscular Myosin-2A (NM2A), APOL1 controls Golgi-derived trafficking of vesicles carrying the lipid scramblase Autophagy-9A (ATG9A). These vesicles deliver APOL3 together with phosphatidylinositol-4-kinase-B (PI4KB) and activated Stimulator of Interferon Genes (STING) to mitochondrion–endoplasmic reticulum (ER) contact sites (MERCSs) for the induction and completion of mitophagy and apoptosis. Through direct interactions with PI4KB and PI4KB activity controllers (Neuronal Calcium Sensor-1, or NCS1, Calneuron-1, or CALN1, and ADP-Ribosylation Factor-1, or ARF1), APOL3 controls PI(4)P synthesis. PI(4)P is required for different processes linked to infection-induced inflammation: (i) STING activation at the Golgi and subsequent lysosomal degradation for inflammation termination; (ii) mitochondrion fission at MERCSs for induction of mitophagy and apoptosis; and (iii) phagolysosome formation for antigen processing. In addition, APOL3 governs mitophagosome fusion with endolysosomes for mitophagy completion, and the APOL3-like murine APOL7C is involved in phagosome permeabilization linked to antigen cross-presentation in dendritic cells. Similarly, APOL3 can induce the fusion of intracellular bacterial membranes, and a role in membrane fusion can also be proposed for endothelial APOLd1 and adipocyte mAPOL6, which promote angiogenesis and adipogenesis, respectively, under inflammatory conditions. Thus, different APOL isoforms play distinct roles in membrane remodeling associated with inflammation. Full article
(This article belongs to the Special Issue Evolution, Structure, and Functions of Apolipoproteins L)
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19 pages, 5928 KiB  
Article
The Influence of Anti-ETAR and Anti-CXCR3 Antibody Levels on the Course of Specific Glomerulonephritis Types
by Maciej Szymczak, Harald Heidecke, Marcelina Żabińska, Łucja Janek, Jakub Wronowicz, Krzysztof Kujawa, Karolina Bukowiec-Marek, Tomasz Gołębiowski, Karolina Skalec, Kai Schulze-Forster, Andrzej Konieczny and Mirosław Banasik
J. Clin. Med. 2024, 13(24), 7752; https://doi.org/10.3390/jcm13247752 - 19 Dec 2024
Viewed by 737
Abstract
Background: Anti-ETAR (endothelin A receptor) antibodies and anti-CXCR3 (C-X-C motif chemokine receptor 3) antibodies are types of non-HLA (human leukocyte antigens) antibodies that could have some influence on the course of glomerulonephritis. The authors aimed to study the influence of these antibodies’ levels [...] Read more.
Background: Anti-ETAR (endothelin A receptor) antibodies and anti-CXCR3 (C-X-C motif chemokine receptor 3) antibodies are types of non-HLA (human leukocyte antigens) antibodies that could have some influence on the course of glomerulonephritis. The authors aimed to study the influence of these antibodies’ levels on the course of specific glomerulonephritis types. Methods: We evaluated the anti-ETAR and anti-CXCR3 antibody levels in the serum of patients with membranous nephropathy (n = 18), focal and segmental glomerulosclerosis (FSGS) (n = 25), systemic lupus erythematosus (n = 17), IgA nephropathy (n = 14), mesangiocapillary glomerulonephritis (n = 6), anti-neutrophil cytoplasmic antibodies (c-ANCA) vasculitis (n = 40), and perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) vasculitis (n = 16), and we compared their levels with the control group (n = 22). Next, we observed the patients’ clinical parameters (serum creatinine, albumin, total protein) for 2 years and checked the correlation of the clinical course markers with basic receptor antibody level. Results: Our results indicate lower anti-ETAR antibody levels in patients with FSGS and IgA nephropathy compared to the control group. Both types of antibodies correlated with creatinine levels after 2 years of observation in IgA nephropathy. Both types of antibodies seemed to negatively influence the total protein and albumin levels in systemic lupus erythematosus. Conclusions: This prospective observation showed that anti-ETAR and anti-CXCR 3 antibody levels are connected with the course of IgA nephropathy and lupus nephritis. Full article
(This article belongs to the Special Issue Glomerulonephritis: Current Diagnosis, Treatment and Future Options)
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11 pages, 507 KiB  
Perspective
Antibodies Against Anti-Oxidant Enzymes in Autoimmune Glomerulonephritis and in Antibody-Mediated Graft Rejection
by Maurizio Bruschi, Giovanni Candiano, Andrea Petretto, Andrea Angeletti, Pier Luigi Meroni, Marco Prunotto and Gian Marco Ghiggeri
Antioxidants 2024, 13(12), 1519; https://doi.org/10.3390/antiox13121519 - 12 Dec 2024
Viewed by 677
Abstract
Historically, oxidants have been considered mechanisms of glomerulonephritis, but a direct cause–effect correlation has never been demonstrated. Several findings in the experimental model of autoimmune conditions with renal manifestations point to the up-regulation of an oxidant/anti-oxidant system after the initial deposition of autoantibodies [...] Read more.
Historically, oxidants have been considered mechanisms of glomerulonephritis, but a direct cause–effect correlation has never been demonstrated. Several findings in the experimental model of autoimmune conditions with renal manifestations point to the up-regulation of an oxidant/anti-oxidant system after the initial deposition of autoantibodies in glomeruli. Traces of oxidants in glomeruli cannot be directly measured for their rapid metabolism, while indirect proof of their implications is derived from the observation that Superoxide Oxidase 2 (SOD2) is generated by podocytes after autoimmune stress. The up-regulation of other anti-oxidant systems takes place as well. Here, we discuss the concept that a second wave of antibodies targeting SOD2 is generated in autoimmune glomerulonephritis and may negatively influence the clinical outcome. Circulating and renal deposits of anti-SOD2 antibodies have been detected in patients with membranous nephropathy and lupus nephritis, two main examples of autoimmune disease of the kidney, which correlate with the clinical outcome. The presence of anti-SOD2 antibodies in circulation and in the kidney has been interpreted as a mechanism which modifies the normal tissue response to oxidative stress. Overall, these findings repropose the role of the oxidant/anti-oxidant balance in autoimmune glomerulonephritis. The same conclusion on the oxidant/anti-oxidant balance may be proposed in renal transplant. Patients receiving a renal graft may develop antibodies specific for Glutathione Synthetase (GST), which modulates the amount of GST disposable for rapid scavenging of reactive oxygen species (ROS). The presence of anti-GST antibodies in serum is a major cause of rejection. The perspective is to utilize molecules with known anti-oxidant effects to modulate the anti-oxidative response in autoimmune pathology of the kidney. A lot of molecules with known anti-oxidant effects can be utilized, many of which have already been proven effective in animal models of autoimmune glomerulonephritis. Many molecules with anti-oxidant activity are natural products; in some cases, they are constituents of diets. Owing to the simplicity of these drugs and the absence of important adverse effects, many anti-oxidants could be directly utilized in human beings. Full article
(This article belongs to the Special Issue Oxidative Stress in Renal Health)
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16 pages, 864 KiB  
Article
Analysis of the Sensitivity and Specificity of Histopathological Findings for Diagnosing Lupus Nephritis
by Epitácio Rafael da Luz Neto, Maria Brandão Tavares, Ana Gabriela de Jesus Torres de Melo, Washington L. C. dos-Santos, Denise Maria Avancini Costa Malheiros and Luís Yu
Diagnostics 2024, 14(23), 2681; https://doi.org/10.3390/diagnostics14232681 - 27 Nov 2024
Viewed by 760
Abstract
Background: Since the introduction of the SLICC criteria in 2012, biopsy-proven lupus nephritis (LN) has been the only independent diagnostic criterion for systemic lupus erythematosus (SLE). This was reaffirmed by the EULAR/ACR in 2019, emphasizing the importance of renal biopsy in LN. However, [...] Read more.
Background: Since the introduction of the SLICC criteria in 2012, biopsy-proven lupus nephritis (LN) has been the only independent diagnostic criterion for systemic lupus erythematosus (SLE). This was reaffirmed by the EULAR/ACR in 2019, emphasizing the importance of renal biopsy in LN. However, the current classification lacks specific histopathological criteria for defining LN. This study describes the histological findings of patients with LN, compares them with those of other glomerular diseases, and evaluates their diagnostic accuracy in a large Latin American population. Methods: This retrospective cohort included 731 kidney biopsies from two distinct academic centers. The patients were divided into two groups as follows: a LN group and a control group comprising patients with membranous nephropathy, IgA nephropathy, membranoproliferative glomerulonephritis, pauci-immune glomerulonephritis, and proliferative glomerulonephritis. Sensitivity and specificity analyses were conducted for various histopathological features. Results: We identified the following five features strongly correlated with LN: mesangial proliferation, subendothelial deposits, C1q staining ≥1+, dominant IgG, and ≥4 positive immunofluorescence elements. Combined, these features yielded an area under the ROC curve of 0.94 (95% CI: 0.91–0.95). These results were validated in a diverse population. In membranous nephropathy, histological features such as mesangial deposits, C1q positivity, and ≥4 positive immunofluorescence elements effectively distinguished class V LN from non-lupus membranous nephropathy, with an area under the ROC curve of 0.85 (95% CI: 0.76–0.93). Conclusions: The combination of mesangial proliferation, subendothelial deposits, C1q staining ≥1+, dominant IgG, and ≥4 positive immunofluorescence elements offer good accuracy for diagnosing renal involvement in SLE in a large Latin American population. In the absence of pathognomonic features, combined criteria are valuable diagnostic tools, particularly when other SLE criteria are lacking. Full article
(This article belongs to the Special Issue Current Issues on Kidney Diseases Diagnosis and Management 2025)
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15 pages, 1266 KiB  
Review
Technology Innovation for Discovering Renal Autoantibodies in Autoimmune Conditions
by Maurizio Bruschi, Giovanni Candiano, Andrea Petretto, Andrea Angeletti, Pier Luigi Meroni, Marco Prunotto and Gian Marco Ghiggeri
Int. J. Mol. Sci. 2024, 25(23), 12659; https://doi.org/10.3390/ijms252312659 - 25 Nov 2024
Viewed by 938
Abstract
Autoimmune glomerulonephritis is a homogeneous area of renal pathology with clinical relevance in terms of its numerical impact and difficulties in its treatment. Systemic lupus erythematosus/lupus nephritis and membranous nephropathy are the two most frequent autoimmune conditions with clinical relevance. They are characterized [...] Read more.
Autoimmune glomerulonephritis is a homogeneous area of renal pathology with clinical relevance in terms of its numerical impact and difficulties in its treatment. Systemic lupus erythematosus/lupus nephritis and membranous nephropathy are the two most frequent autoimmune conditions with clinical relevance. They are characterized by glomerular deposition of circulating autoantibodies that recognize glomerular antigens. Technologies for studying renal tissue and circulating antibodies have evolved over the years and have culminated with the direct analysis of antigen–antibody complexes in renal bioptic fragments. Initial studies utilized renal microdissection to obtain glomerular tissue. Obtaining immunoprecipitates after partial proteolysis of renal tissue is a recent evolution that eliminates the need for tissue microdissection. New technologies based on ‘super-resolution microscopy’ have added the possibility of a direct analysis of the interaction between circulating autoantibodies and their target antigens in glomeruli. Peptide and protein arrays represent the new frontier for identifying new autoantibodies in circulation. Peptide arrays consist of 7.5 million aligned peptides with 16 amino acids each, which cover the whole human proteome; protein arrays utilize, instead, a chip containing structured proteins, with 26.000 overall. An example of the application of the peptide array is the discovery in membranous nephropathy of many new circulating autoantibodies including formin-like-1, a protein of podosomes that is implicated in macrophage movements. Studies that utilize protein arrays are now in progress and will soon be published. The contribution of new technologies is expected to be relevant for extending our knowledge of the mechanisms involved in the pathogenesis of several autoimmune conditions. They may also add significant tools in clinical settings and modify the therapeutic handling of conditions that are not considered to be autoimmune. Full article
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24 pages, 2418 KiB  
Review
Epitope Spreading in Immune-Mediated Glomerulonephritis: The Expanding Target
by Camillo Tancredi Strizzi, Martina Ambrogio, Francesca Zanoni, Bibiana Bonerba, Maria Elena Bracaccia, Giuseppe Grandaliano and Francesco Pesce
Int. J. Mol. Sci. 2024, 25(20), 11096; https://doi.org/10.3390/ijms252011096 - 16 Oct 2024
Viewed by 1824
Abstract
Epitope spreading is a critical mechanism driving the progression of autoimmune glomerulonephritis. This phenomenon, where immune responses broaden from a single epitope to encompass additional targets, contributes to the complexity and severity of diseases such as membranous nephropathy (MN), lupus nephritis (LN), and [...] Read more.
Epitope spreading is a critical mechanism driving the progression of autoimmune glomerulonephritis. This phenomenon, where immune responses broaden from a single epitope to encompass additional targets, contributes to the complexity and severity of diseases such as membranous nephropathy (MN), lupus nephritis (LN), and ANCA-associated vasculitis (AAV). In MN, intramolecular spreading within the phospholipase A2 receptor correlates with a worse prognosis, while LN exemplifies both intra- and intermolecular spreading, exacerbating renal involvement. Similarly, ANCA reactivity in AAV highlights the destructive potential of epitope diversification. Understanding these immunological cascades reveals therapeutic opportunities—targeting early epitope spreading could curb disease progression. Despite promising insights, the clinical utility of epitope spreading as a prognostic tool remains debated. This review provides a complete overview of the current evidence, exploring the dual-edged nature of epitope spreading, the intricate immune mechanisms behind it, and its therapeutic implications. By elucidating these dynamics, we aim to pave the way for more precise, targeted interventions in autoimmune glomerular diseases. Full article
(This article belongs to the Special Issue Molecular Advances in Glomerular Diseases)
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15 pages, 1351 KiB  
Review
Endothelin Inhibitors in Chronic Kidney Disease: New Treatment Prospects
by Agata Rakotoarison, Marta Kepinska, Andrzej Konieczny, Karolina Władyczak, Dariusz Janczak, Agnieszka Hałoń, Piotr Donizy and Mirosław Banasik
J. Clin. Med. 2024, 13(20), 6056; https://doi.org/10.3390/jcm13206056 - 11 Oct 2024
Cited by 1 | Viewed by 1939
Abstract
The endothelin system is reported to play a significant role in glomerular and tubulointerstitial kidney disease. In the kidney, endothelins are produced in mesangial cells and the glomerular basement membrane by the endothelium and podocytes. The endothelin system regulates glomerular function by inducing [...] Read more.
The endothelin system is reported to play a significant role in glomerular and tubulointerstitial kidney disease. In the kidney, endothelins are produced in mesangial cells and the glomerular basement membrane by the endothelium and podocytes. The endothelin system regulates glomerular function by inducing proliferation, increasing permeability and in effect proteinuria, and stimulating inflammation, tubular fibrosis, and glomerular scarring. Endothelin A receptor antagonists have been proven to delay the progression of chronic kidney disease and play a protective role in immunoglobulin A nephropathy, focal segmental glomerulosclerosis, and diabetic nephropathy. There are several ongoing research studies with ETAR antagonists in nondiabetic nephropathy, Alport disease, vasculitis and scleroderma nephropathy, which results are promising. Some reports suggest that the endothelin system might contribute to ischemia–reperfusion injury, acute graft rejection and deterioration of graft function. Endothelin inhibition in renal transplantation and its influence on graft survival is the future direction needing further research. The most frequent side effects associated with ETAR antagonists is fluid retention. Additionally, it should be considered if selective ETAR antagonists therapy needs to be co-administered with sodium-glucose co-transporter 2 inhibitors, renin–angiotensin–aldosterone inhibitors or diuretics and which patients should be recruited to such treatment to minimize the risk of adverse outcomes. Full article
(This article belongs to the Section Nephrology & Urology)
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40 pages, 1887 KiB  
Review
An Updated Comprehensive Review on Diseases Associated with Nephrotic Syndromes
by Ralph Wendt, Alina Sobhani, Paul Diefenhardt, Moritz Trappe and Linus Alexander Völker
Biomedicines 2024, 12(10), 2259; https://doi.org/10.3390/biomedicines12102259 - 4 Oct 2024
Viewed by 7960
Abstract
There have been exciting advances in our knowledge of primary glomerular diseases and nephrotic syndromes in recent years. Beyond the histological pattern from renal biopsy, more precise phenotyping of the diseases and the use of modern nephrogenetics helps to improve treatment decisions and [...] Read more.
There have been exciting advances in our knowledge of primary glomerular diseases and nephrotic syndromes in recent years. Beyond the histological pattern from renal biopsy, more precise phenotyping of the diseases and the use of modern nephrogenetics helps to improve treatment decisions and sometimes also avoid unnecessary exposure to potentially toxic immunosuppression. New biomarkers have led to easier and more accurate diagnoses and more targeted therapeutic decisions. The treatment landscape is becoming wider with a pipeline of promising new therapeutic agents with more sophisticated approaches. This review focuses on all aspects of entities that are associated with nephrotic syndromes with updated information on recent advances in each field. This includes podocytopathies (focal segmental glomerulosclerosis and minimal-change disease), membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, fibrillary glomerulonephritis, amyloidosis, and monoclonal gammopathy of renal significance in the context of the nephrotic syndrome, but also renal involvement in systemic diseases, diabetic nephropathy, and drugs that are associated with nephrotic syndromes. Full article
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11 pages, 3096 KiB  
Article
Soluble Epoxide Hydrolase Inhibition Attenuates Proteinuria by Alleviating Renal Inflammation and Podocyte Injuries in Adriamycin-Induced Nephropathy
by Qingyu Niu, Ziyu Guo, Yaoxian Liang and Li Zuo
Int. J. Mol. Sci. 2024, 25(19), 10629; https://doi.org/10.3390/ijms251910629 - 2 Oct 2024
Viewed by 1366
Abstract
Soluble epoxide hydrolase (sEH) has previously been demonstrated to play an important part in kidney diseases by hydrolyzing renoprotective epoxyeicosatrienoic acids to their less active diols. However, little is known about the role of sEH in primary glomerular diseases. Here, we investigated the [...] Read more.
Soluble epoxide hydrolase (sEH) has previously been demonstrated to play an important part in kidney diseases by hydrolyzing renoprotective epoxyeicosatrienoic acids to their less active diols. However, little is known about the role of sEH in primary glomerular diseases. Here, we investigated the effects of sEH inhibition on proteinuria in primary glomerular diseases and the underlying mechanism. The expression of sEH in the renal tubules of patients with minimal change disease, IgA nephropathy, and membranous nephropathy was significantly increased. Renal sEH expression level was positively correlated with the 24 h urine protein excretion and negatively correlated with serum albumin. In the animal model of Adriamycin (ADR)-induced nephropathy, renal sEH mRNA and protein expression increased significantly. Pharmacological inhibition of sEH with AUDA effectively reduced urine protein excretion and attenuated renal pathological damage. Furthermore, sEH inhibition markedly abrogated the abnormal expressions of nephrin and desmin in glomerular podocytes induced by ADR. More importantly, AUDA treatment inhibited renal NF-κB activation and reduced TNF-α levels in rats with ADR-induced nephropathy. Overall, our findings suggest that sEH inhibition ameliorates renal inflammation and podocyte injury, thus reducing proteinuria and exerting renoprotective effects. Targeting sEH might be a potential strategy for the treatment of proteinuria in primary glomerular diseases. Full article
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25 pages, 471 KiB  
Review
Renal Manifestations of Chronic Hepatitis C: A Review
by Aalam Sohal, Carol Singh, Akshita Bhalla, Harsimran Kalsi and Marina Roytman
J. Clin. Med. 2024, 13(18), 5536; https://doi.org/10.3390/jcm13185536 - 18 Sep 2024
Viewed by 2192
Abstract
Hepatitis C virus (HCV) has emerged as a major global health concern and, if left untreated, can lead to significant liver damage, including cirrhosis, decompensated liver disease, and hepatocellular carcinoma (HCC). Approximately 40% of patients with HCV infection experience extrahepatic manifestations, including renal [...] Read more.
Hepatitis C virus (HCV) has emerged as a major global health concern and, if left untreated, can lead to significant liver damage, including cirrhosis, decompensated liver disease, and hepatocellular carcinoma (HCC). Approximately 40% of patients with HCV infection experience extrahepatic manifestations, including renal involvement. HCV-related renal disease is of significant importance among patients with chronic kidney disease (CKD), leading to higher morbidity and mortality. The renal damage due to HCV infection primarily results from cryoglobulinemia and glomerulonephritis, with conditions such as membranoproliferative glomerulonephritis (MPGN) and membranous nephropathy (MN) being most prevalent. Despite advancements in treatment, including the use of directly acting antiviral agents (DAAs), renal complications remain a significant burden in untreated patients. HCV-positive patients on hemodialysis (HD) or those who have undergone kidney transplantation face increased mortality rates compared to their HCV-negative counterparts. Managing HCV infection before kidney transplantation is crucial to mitigate the risk of HCV-related renal complications. Conversely, kidney transplantation from HCV-infected donors is well established, as post-transplant treatment for HCV is safe and effective, potentially reducing mortality and morbidity for patients on transplant waiting lists. This review aims to provide a comprehensive analysis of the renal manifestations of HCV, emphasizing the importance of early diagnosis and treatment to improve patient outcomes. Full article
(This article belongs to the Section Gastroenterology & Hepatopancreatobiliary Medicine)
15 pages, 1513 KiB  
Review
Mitochondrial Dysfunction in Aristolochic Acid I-Induced Kidney Diseases: What We Know and What We Do Not Know
by Alexandra T. Lukinich-Gruia, Crenguta L. Calma, Flavia A. E. Szekely, Iustina-Mirabela Cristea, Maria-Alexandra Pricop, Alina-Georgiana Simina, Valentin L. Ordodi, Nikola M. Pavlović, Calin A. Tatu and Virgil Paunescu
Appl. Sci. 2024, 14(17), 7961; https://doi.org/10.3390/app14177961 - 6 Sep 2024
Cited by 1 | Viewed by 974
Abstract
Aristolochic acids, compounds derived from Aristolochiaceae plant species, are associated with significant renal nephrotoxicity and carcinogenicity. Aristolochic acid I (AAI), the most predominant and potent of these compounds, is a primary etiological agent in acute and chronic kidney diseases such as Aristolochic Acid [...] Read more.
Aristolochic acids, compounds derived from Aristolochiaceae plant species, are associated with significant renal nephrotoxicity and carcinogenicity. Aristolochic acid I (AAI), the most predominant and potent of these compounds, is a primary etiological agent in acute and chronic kidney diseases such as Aristolochic Acid Nephropathy (AAN) and Balkan Endemic Nephropathy (BEN). Due to the kidneys’ critical role in xenobiotic excretion, they are the primary organs affected by AAI toxicity. Recent in vitro and in vivo studies have highlighted mitochondrial dysfunction as a crucial factor in the pathogenesis of these kidney diseases. This review provides an update on the recent advances in understanding the causes of acquired mitochondrial dysfunction within the context of AAN and BEN. Key findings include the identification of mitochondrial DNA depletion, loss of mitochondrial membrane potential, and decreased ATP production as significant contributors to kidney damage. Additionally, oxidative stress markers and inflammatory mediators have been implicated in disease progression. Potential therapeutic approaches, such as the use of antioxidants like vitamin C and catalpol, have shown promise in mitigating AAI-induced cytotoxicity. Furthermore, future predictive approaches like pharmacogenomics could pave the way for novel mitochondria-targeted treatments. A comprehensive characterization of mitochondrial function, its underlying molecular mechanisms, and specific biomarkers could offer valuable insights and potential therapeutic options, significantly impacting the current management of AAN and BEN. Full article
(This article belongs to the Section Applied Biosciences and Bioengineering)
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