Molecular Mechanisms of Kidney Injury and Repair

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(3), P. 1542 - 1542

Published: Jan. 28, 2022

Chronic kidney disease (CKD) will become the fifth global cause of death by 2040, thus emphasizing need to better understand molecular mechanisms damage and regeneration in kidney. CKD predisposes acute injury (AKI) which, turn, promotes progression. This implies that or AKI-to-CKD transition are associated with dysfunctional repair mechanisms. Current therapeutic options slow progression but fail treat accelerate recovery from AKI unable promote regeneration. Unraveling cellular involved repair, including failure this process, may provide novel biomarkers tools. We now review contribution different events transition, focusing on role macrophages injury, forms regulated cell necroinflammation, senescence senescence-associated secretory phenotype (SAPS), polyploidization, podocyte activation parietal epithelial cells. Next, we discuss key contributors opportunities for their manipulation, a focus resident renal progenitor cells, stem cells reparative secretome, certain macrophage subphenotypes within M2 senescent clearance.

Language: Английский

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Accumulation of α-synuclein mediates podocyte injury in Fabry nephropathy

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(11)

Published: April 4, 2023

Current therapies for Fabry disease are based on reversing intracellular accumulation of globotriaosylceramide (Gb3) by enzyme replacement therapy (ERT) or chaperone-mediated stabilization the defective enzyme, thereby alleviating lysosomal dysfunction. However, their effect in reversal end-organ damage, like kidney injury and chronic disease, remains unclear. In this study, ultrastructural analysis serial human biopsies showed that long-term use ERT reduced Gb3 podocytes but did not reverse podocyte injury. Then, a CRISPR/Cas9-mediated α-galactosidase knockout cell line confirmed ERT-mediated without resolution Transcriptome-based connectivity mapping SILAC-based quantitative proteomics identified α-synuclein (SNCA) as key event mediating Genetic pharmacological inhibition SNCA improved structure function podocytes, exceeding benefits ERT. Together, work reconceptualizes Fabry-associated beyond accumulation, introduces modulation potential intervention, especially patients with nephropathy.

Language: Английский

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Pathogenesis and Molecular Mechanisms of Anderson–Fabry Disease and Possible New Molecular Addressed Therapeutic Strategies

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(18), P. 10088 - 10088

Published: Sept. 18, 2021

Anderson–Fabry disease (AFD) is a rare with an incidenceof approximately 1:117,000 male births. Lysosomal accumulation of globotriaosylceramide (Gb3) the element characterizing Fabry due to hereditary deficiency α-galactosidase A (GLA) enzyme. The Gb3 causes lysosomal dysfunction that compromises cell signaling pathways. Deposition sphingolipids occurs in autonomic nervous system, dorsal root ganglia, kidney epithelial cells, vascular system and myocardial resulting organ failure. This manuscript will review molecular pathogenetic pathways involved its damage. Some studies reported inhibition mitochondrial function energy metabolism plays significant role AFD cardiomyopathy patients. Furthermore, has been as linked dysregulation autophagy–lysosomal pathway which inhibits mechanistic target rapamycin kinase (mTOR) mediated control cells. Cerebrovascular complications are caused by cerebral micro vessel stenosis. These wall thickening from intramural glycolipids, luminal occlusion or thrombosis. Other mechanisms damage endocytosis degradation endothelial calcium-activated intermediate-conductance potassium ion channel 3.1 (KCa3.1) via clathrin-dependent process. process represents crucial event dysfunction. Several have identified deacylated form Gb3, globotriaosylsphingosine (Lyso-Gb3), main catabolite increases plasma urine patients AFD. mean concentrations all organs Galactosidase knockout mice were significantly higher than those wild-type mice. distributions isoforms vary organ. Various observed mainly kidneys, kidney-specific hydroxylated. action on KCa3.1 suggests possible contribution this interaction process, expressed various including fibroblasts, smooth muscle cells proliferation, microglia, lymphocytes. could be considered potential therapeutic correct enzyme addition traditional replacement therapies (ERT) drug chaperone therapy.

Language: Английский

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An expert consensus on the recommendations for the use of biomarkers in Fabry disease

Molecular Genetics and Metabolism, Journal Year: 2023, Volume and Issue: 139(2), P. 107585 - 107585

Published: April 18, 2023

Fabry disease is an X-linked lysosomal storage disorder caused by the accumulation of glycosphingolipids in various tissues and body fluids, leading to progressive organ damage life-threatening complications. Phenotypic classification based on progression severity can be used predict outcomes. Patients with a classic phenotype have little no residual α-Gal A activity widespread involvement, whereas patients later-onset limited single organ, often heart. Diagnosis monitoring should therefore individualized, biomarkers are available support this. Disease-specific useful diagnosis disease; non-disease-specific may assess damage. For most it challenging prove they translate differences risk clinical events associated disease. Therefore, careful treatment outcomes collection prospective data needed. As we deepen our understanding disease, important regularly re-evaluate appraise published evidence relating biomarkers. In this article, present results literature review between February 2017 July 2020 impact disease-specific provide expert consensus recommendations for use those

Language: Английский

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Modeling of Fabry disease nephropathy using patient derived human induced pluripotent stem cells and kidney organoid system

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: Feb. 22, 2023

Abstract Objectives To explore the possibility of kidney organoids generated using patient derived human induced pluripotent stem cells (hiPSC) for modeling Fabry disease nephropathy (FDN). Methods First, we hiPSC line peripheral blood mononuclear (PBMCs) from two male FD-patients with different types GLA mutation: a classic type mutation (CMC-Fb-001) and non-classic (CMC-Fb-003) mutation. Second, wild-type (WT) (WTC-11) mutant hiPSCs (CMC-Fb-001 CMC-Fb-003). We then compared alpha-galactosidase A (α-GalA) activity, deposition globotriaosylceremide (Gb-3), zebra body formation under electromicroscopy (EM). Results Both FD patients had same mutations as those detected in PBMCs patients, showing typical pluripotency markers, normal karyotyping, successful tri-lineage differentiation. Kidney WT-hiPSC both expressed nephron markers without structural deformity. Activity α-GalA was decreased Gb-3 increased comparison WT, such changes being far more significant CMC-Fb-001 than CMC-Fb-003. In EM finding, multi-lammelated inclusion CMC-Fb-003 organoids, but not WT. Conclusions might recapitulate phenotype represent severity according to type.

Language: Английский

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Renal Manifestations of Fabry Disease: A Narrative Review

Canadian Journal of Kidney Health and Disease, Journal Year: 2021, Volume and Issue: 8, P. 205435812098562 - 205435812098562

Published: Jan. 1, 2021

In this narrative review, we describe general aspects, histological alterations, treatment, and implications of Fabry disease (FD) nephropathy. This information should be used to guide physicians patients in a shared decision-making process.Original peer-reviewed articles, review opinion pieces were identified from PubMed Google Scholar databases. Only sources English accessed.We performed focused assessing the main aspects FD The literature was critically analyzed theoretical contextual perspective, thematic analysis performed.FD nephropathy is related progressive accumulation GL3, which occurs all types renal cells. It more prominent podocytes, seem play an important role pathogenesis A precise detection disorders fundamental importance because specific treatment usually delayed, making reversibility unlikely leading worse prognosis.As no formal tool applied assess quality included studies, selection bias may have occurred. Nonetheless, attempted provide comprehensive on topic using current studies experts extensive literature.Dans cette revue narrative, nous discutons des généraux, modifications histologiques, du traitement et de la néphropathie liée à Maladie Fabry. Des informations qui serviront guider les médecins dans un processus commun prise décision.Les originaux d’articles évalués par pairs, d’articles-synthèses d’opinion ont été répertoriés bases données Pubmed Scholar. Seuls articles en anglais consultés.Nous avons procédé une ciblée examinant principaux liés maladie La documentation fait l’objet d’une critique rigoureuse point vue théorique contextuel, analyse thématique effectuée.La est associée l’accumulation se produit tous cellules rénales. Elle plus présente semblent jouer rôle pathogenèse néphropathie. Un dépistage précis troubles rénaux capitale puisque le spécifique généralement retardé, ce rend réversibilité peu probable conduit pronostic défavorable.Des biais sélection pourraient s’être introduits puisqu’aucun outil formel n’a utilisé pour évaluer études incluses. Nous néanmoins tenté procéder examen complet sujet grâce aux actuelles menées approfondie documentation.

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Gene therapy for Fabry disease: Progress, challenges, and outlooks on gene-editing

Molecular Genetics and Metabolism, Journal Year: 2021, Volume and Issue: 134(1-2), P. 117 - 131

Published: July 21, 2021

Language: Английский

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Pathology and pathogenic pathways in fabry nephropathy

Clinical and Experimental Nephrology, Journal Year: 2021, Volume and Issue: 25(9), P. 925 - 934

Published: March 26, 2021

Language: Английский

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Long-term follow-up of renal function in patients treated with migalastat for Fabry disease

Molecular Genetics and Metabolism Reports, Journal Year: 2021, Volume and Issue: 28, P. 100786 - 100786

Published: Aug. 4, 2021

The effect of migalastat on long-term renal outcomes in enzyme replacement therapy (ERT)-naive and ERT-experienced patients with Fabry disease is not well defined. An integrated posthoc analysis the phase 3 clinical trials open-label extension studies was conducted to evaluate changes function amenable GLA variants who were treated for ≥2 years during these studies. included ERT-naive (n = 36 [23 females]; mean age 45 years; baseline estimated glomerular filtration rate (eGFR), 91.4 mL/min/mL/1.73 m2) 42 [24 age, 50 eGFR, 89.2 mL/min/1.73m2) received 123 mg every other day years. annualized change from last observation using Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI) calculated by both simple linear regression a random coefficient model. In patients, rates eGFRCKD-EPI - 1.6 mL/min/1.73 m2 overall 1.8 1.4 male female respectively, as regression. 2.6 0.8 respectively. Mean classic phenotype (defined white blood cell alpha galactosidase A [α-Gal A] activity <3% normal multiorgan system involvement) -1.7 m2. When model, which adjusted sex, function, minimal (mean: -0.1 0.1 respectively). conclusion, receiving treatment (≤8.6 years) maintained irrespective status, or phenotype.

Language: Английский

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Lysosome function in glomerular health and disease

Cell and Tissue Research, Journal Year: 2021, Volume and Issue: 385(2), P. 371 - 392

Published: Jan. 12, 2021

Abstract The lysosome represents an important regulatory platform within numerous vesicle trafficking pathways including the endocytic, phagocytic, and autophagic pathways. Its ability to fuse with endosomes, phagosomes, autophagosomes enables break down a wide range of both endogenous exogenous cargo, macromolecules, certain pathogens, old or damaged organelles. Due its center position in intricate network events, has emerged as central signaling node for sensing orchestrating cells metabolism immune response, inter-organelle inter-cellular membrane repair. This review highlights current knowledge general function discusses these findings their implication renal glomerular cell types health disease involvement lysosomal storage diseases role lysosomes nongenetic injuries.

Language: Английский

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