High Lyso-Gb3 Plasma Levels Associated with Decreased miR-29 and miR-200 Urinary Excretion in Young Non-Albuminuric Male Patient with Classic Fabry Disease

Jaurretche, Sebastián; Pérez, Germán; Venera, Graciela Delia

doi:10.1155/2019/4980942

Cited by 5 publications

(4 citation statements)

References 15 publications

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“…The concentration of circulating miRNAs in plasma including miR-21 and miR-210 were found to be reduced in patients with chronic renal failure, while no correlation was observed between urinary miRNAs and kidney function 31 . In a recent case study of a young Fabry patient without nephropathy manifestations, the expression level of miR-29 and miR-200 were found to be decreased in urinary sediment while the other TGF-β related miRNAs not 32 . Taken together, although TGF-β signalling pathway was suggested to be associated with Fabry nephropathy 12,28 , there is no direct evidence to support the putative involvement of TGF-β regulated miRNAs in ERT treatment.…”

Section: Discussionmentioning

confidence: 96%

Circulating microRNAs in Fabry Disease

Hoepfner

et al. 2019

Sci Rep

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Fabry disease is an X-linked deficiency of the lysosomal hydrolase alpha-galactosidase A (alpha-Gal).This results in an accumulation of globotriaosylceramide (GL-3/Gb3) in a variety of cells with subsequent functional impairment. The continuous progress of FD often leads to decreased quality of life and premature death caused by multi-organic complications. The overall aim of our study was to determine the amount of circulating miRNAs in Fabry patients and to test whether ERT would alter the level of individual circulating miRNAs. We used miRNA sequencing by the HTG EdgeSeq System to identify the circulating miRNA pool from Fabry patients with and without enzyme replacement therapy (n = 6). In total, 296 miRNAs in serum of patients were identified. Among them 9 miRNAs were further evaluated in extra serum samples (n = 31) using real-time qPCR and 6 of them showed significant differential expression. The resulting miRNA pattern may help to better understand mechanisms involved in the beneficial effects of ERT and these new miRNA markers could help to estimate the efficacy of ERT or to identify Fabry patients with specific need for ERT.Fabry disease (FD) is an X-chromosome linked disorder caused by mutations in gene GLA coding for alpha-galactosidase-A enzyme (alpha-Gal). The enzyme activity deficiency that results in an accumulation of globotriaosylceramide (GL-3/Gb3) in a variety of cells often leads to subsequent functional impairment 1 . The initial manifestations of Fabry disease usually start in adolescence stage of life, including neuropathic pain (acroparesthesia) and abdominal discomfort 2 . The continuous progress of FD results in decreased quality of life and premature death caused by multi-organic complications 3,4 . As a specific treatment, Enzyme replacement therapy (ERT) has been shown to stabilize and reduce many signs and symptoms of Fabry disease 5-7 . More recently, oral chaperone therapy was shown to be also effective in selected Fabry patients depending on the underlying gene mutation 8 . Of clinical importance is the fact that early diagnosis and treatment in the disease course may delay or prevent the progression towards irreversible organ dysfunction and the consequent life-threatening complications. This is sometimes difficult due to the high variability of the severity and multi-organ system involvement in Fabry disease 9 . Next to the clinical features, enzyme activity tests and DNA sequencing are available to confirm the diagnosis 10 . Globotriaosylsphingosine (LysoGb3) serves as a useful biomarker to improve the diagnosis of heterozygous Fabry disease for therapeutic evaluation and monitoring 11 . In addition, circulating serum proteins in the blood of Fabry patients may help to get more information about the underlying pathophysiological mechanisms 12 .Recently, a group of small RNA molecules known as microRNAs (miRNAs) have been proved to play essential roles in the cardiac function 13,14 . Moreover, the expression levels of miRNAs that present in circulating fluid usually differ betw...

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Section: Discussionmentioning

confidence: 96%

Circulating microRNAs in Fabry Disease

Hoepfner

et al. 2019

Sci Rep

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“…Decreased expression of miR-29a-3p or/and miR-200a-3p was found in 4 out of 12 FD patients [ 48 ]. They also reported decreased expression of both miRNAs in a case report of a young male patient with classic FD [ 49 ]. However, we found no significant differences in the expression of selected uEV-derived miRNAs between FD patients with and without Fabry nephropathy at last follow-up, including the expression of miR-29a-3p and miR-200a-3p.…”

Section: Discussionmentioning

confidence: 99%

Urinary Extracellular Vesicles and Their miRNA Cargo in Patients with Fabry Nephropathy

Levstek

Mlinšek

Holcar

et al. 2021

Genes

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Current biomarkers of Fabry nephropathy lack sensitivity in detecting early kidney damage and do not predict progression of nephropathy. Urinary extracellular vesicles (uEVs) and their molecular cargo could reflect early changes in renal impairment as they are secreted by the cells lining the urinary tract. We aimed to conduct a proof-of-concept study to investigate whether analysis of uEV characteristics and expression of uEV-derived microRNAs (miRNAs) could be applicable in studies to predict the development and progression of nephropathy in Fabry disease. A total of 20 Fabry patients were divided into two groups, depending on the presence of nephropathy. Chronological urine samples collected during 10-year follow-up were used for uEVs isolation with size exclusion chromatography. Nanoparticle tracking analysis was used to determine concentration and size of uEVs. We evaluated the expression of five uEV-derived miRNAs by qPCR (miR-23a-3p, miR-29a-3p, miR-30b-5p, miR-34a-5p, miR-200a-3p). There was no difference in the concentration and size of uEVs between patients with and without nephropathy at last follow-up or longitudinally. However, we found increased expression of miR-29a-3p and miR-200a-3p in uEVs isolated from chronological samples of patients with Fabry nephropathy. This may indicate an attempt by the organism to prevent the progression of renal damage leading to end-stage renal disease as previously reported in type 1 diabetes. In addition, we found an increased expression of miR-30b-5p in the 10-year period in uEVs of patients without renal dysfunction. miR-30b-5 was reported to have a protective role in podocyte injury and may possibly be important in Fabry nephropathy. These findings indicate that uEVs and their molecular cargo could be a promising target of studies focusing on elucidation of Fabry nephropathy. Nevertheless, total concentration and size of uEVs were neither indicative of the presence nor progression of Fabry nephropathy, while the role of the analyzed miRNAs in Fabry nephropathy progression was merely indicated and needs further in-depth studies.

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“…Another field of investigation is the analysis of transcriptomics focusing on some selected urinary miRNA characterized by a higher or lower degree of expression in AFD. A decrease in certain miRNA species, such asmiR-29 and miR-200, has been associated with renal fibrosis prior to the onset of pathological albuminuria [ 69 ]. Some serum miRNAs such asmiR-1307-5p, miR-21-5p, miR-152-5p, and miR-26a-5p have been reported as significantly down-regulated in Anderson–Fabry patients.…”

Section: Molecular Pathogenesis Of Renal Involvement In Anderson–fabry Diseasementioning

confidence: 99%

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

Tuttolomondo

Simonetta

Riolo

et al. 2021

IJMS

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

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High Lyso-Gb3 Plasma Levels Associated with Decreased miR-29 and miR-200 Urinary Excretion in Young Non-Albuminuric Male Patient with Classic Fabry Disease

Cited by 5 publications

References 15 publications

Circulating microRNAs in Fabry Disease

Circulating microRNAs in Fabry Disease

Urinary Extracellular Vesicles and Their miRNA Cargo in Patients with Fabry Nephropathy

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

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