Pathogenesis and therapy of focal segmental glomerulosclerosis: an update. Pediatr Nephrol

Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
Pediatric Nephrology (Impact Factor: 2.86). 11/2010; 26(7):1001-15. DOI: 10.1007/s00467-010-1692-x
Source: PubMed


Focal and segmental glomerulosclerosis (FSGS) is an important cause of steroid-resistant nephrotic syndrome in adults and children. It is responsible for 5-20% of all cases of end-stage kidney disease (ESKD) in the United States. The pathogenesis of FSGS has not been fully elucidated; however, data from molecular studies of familial cases in the last two decades suggest that FSGS is a defect of the podocyte. The therapeutic agents available for treatment of FSGS are not very effective and only a small percentage of affected individuals will achieve complete remission. Recent data from molecular biology and molecular genetics has provided insight into the mechanisms of action of old agents and also identification of other novel therapeutic targets. This review focuses on recent advances in the molecular pathogenesis of FSGS and currently available therapeutic agents as well as potential novel therapies.

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    • "Data obtained from rat FSGS model indicated that thymosin beta 4, which was increased in sclerotic glomeruli and predominantly localized in endothelial cells, could be considered as a marker in early sclerotic event and may contribute to sclerosis [7]. Other studies on FSGS familial cases and some animal experiments have shown that podocyte depletion or damages in its functional integrity is central to the initiation and progression of the sclerotic lesion [8]. Genetic analysis revealed a strong association of APOL1 variants with susceptibility to FSGS and HIV-associated nephropathy among African Americans [9]. "
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    ABSTRACT: Since glomerular sclerosis frequently accompanies various glomerular diseases at the end stages, it is challenging to differentiate ubiquitous biological processes underlying this pathology from those critically involved in specific diseases. Furthermore, in-depth proteomic profile of human glomerular sclerosis remains limited. In this study, human glomeruli with intermediate (i-GS) and advanced (GS) sclerotic lesions, which were excluded from specific renal diseases and assumed to be aging-related, were laser captured from macroscopically normal cortex distant from urological carcinoma, and subjected to label-free quantitative proteomic analysis. We explicate an evident increase of membrane attack complex in i-GS and GS with an up-going tendency, which is accompanied by increasing of inhibitory regulators of alternative and terminal pathways. GO annotation and IPA pathway analysis agree to these results. Proteomic findings are validated by immunohistochemical studies which indicate that alternative and terminal pathways are positively involved in the glomerular sclerosis seen in distinct renal diseases. Furthermore, proteomic analysis also demonstrates remarkable increases of complement factor B in GS and TGF-ß1 in both GS and i-GS. Identification of complement factor B implicates that on-site activation of alternative pathway may occur in injured glomeruli and stepwise increase of TGF-ß1 suggests its contribution to the progression of glomerulosclerosis. This study provides in-depth quantitative proteomic profiles of human glomeruli with intermediate and advanced sclerotic lesions. It reveals that the over-expression of alternative and terminal pathway components is significantly involved in human glomerulosclerosis seen in distinct renal diseases. Proteomic identification of the increased TGF-ß1 provides supporting evidence for the role of podocyte apoptosis leading to human glomerulosclerosis. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of proteomics 03/2015; 123. DOI:10.1016/j.jprot.2015.03.024 · 3.89 Impact Factor
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    • "The highly dynamic podocyte slit diaphragm and associated actin cytoskeleton are responsible for maintaining the foot process architecture 3. Genetic mutations of different actin cytoskeletal and slit-associated proteins cause nephrotic syndrome and foot process effacement in humans. Most of these mutations show histopathological lesions consistent with focal segmental glomerulosclerotic (FSGS) 4,5. FSGS, however most commonly occurs secondary to glomerular hyperfiltration in the setting of low nephron number, obesity, viral infection (HIV) or medication use 6. "
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    ABSTRACT: In contrast to most glomerular diseases, the injury pattern in focal segmental glomerulosclerosis (FSGS) is highly heterogeneous, even though podocytes are genetically identical and exposed to the same environmental factors. To understand changes in individual podocytes, we generated and analyzed a stochastic multicolor Cre-reporter, encoding four fluorescent proteins. In these animals, podocytes were randomly labeled allowing individual cells and their foot processes to be distinguished. In healthy animals, podocyte size and structure showed little cell to cell variability. In the doxorubicin-induced FSGS model, fluorescent-labeled glomerular podocyte numbers decreased and fluorescent cells could be recovered from the urine. The size of the remaining podocytes showed a high degree of heterogeneity, some cells remained small, while others enlarged. Both enlarged and non-enlarged podocytes showed alterations in their foot process morphology. Thus, by the virtue of a multicolor cre-reporter, individual podocytes could be viewed in real time at a cellular resolution indicating a heterogeneous podocyte injury response during the pathogenesis of FSGS.Kidney International advance online publication, 27 November 2013; doi:10.1038/ki.2013.463.
    Kidney International 11/2013; 85(4). DOI:10.1038/ki.2013.463 · 8.56 Impact Factor
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    • "Focal segmental glomerulosclerosis (FSGS) was first described in kidney biopsy of adults with nephrotic syndrome by Fahr in 1925, and in 1957 Rich observed that sclerosis classically start from the corticomedullary junction before involving other parts of the renal cortex in children with nephrotic syndrome (NS) [1]–[3]. FSGS is a pathological entity which is characterized by idiopathic steroid-resistant nephrotic syndrome (SRNS) and progression to end-stage renal disease (ESRD) in the majority of affected individuals. "
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    ABSTRACT: Primary focal segmental glomerulosclerosis (FSGS) is pathological entity which is characterized by idiopathic steroid-resistant nephrotic syndrome (SRNS) and progression to end-stage renal disease (ESRD) in the majority of affected individuals. Currently, there is no practical noninvasive technique to predict different pathological types of glomerulopathies. In this study, the role of urinary metabolomics in the diagnosis and pathogenesis of FSGS was investigated. NMR-based metabolomics was applied for the urinary metabolic profile in the patients with FSGS (n = 25), membranous nephropathy (MN, n = 24), minimal change disease (MCD, n = 14) and IgA nephropathy (IgAN, n = 26), and healthy controls (CON, n = 35). The acquired data were analyzed using principal component analysis (PCA) followed by orthogonal projections to latent structure discriminant analysis (OPLS-DA). Model validity was verified using permutation tests. FSGS patients were clearly distinguished from healthy controls and other three types of glomerulopathies with good sensitivity and specificity based on their global urinary metabolic profiles. In FSGS patients, urinary levels of glucose, dimethylamine and trimethylamine increased compared with healthy controls, while pyruvate, valine, hippurate, isoleucine, phenylacetylglycine, citrate, tyrosine, 3-methylhistidine and β-hydroxyisovalerate decreased. Additionally, FSGS patients had lower urine N-methylnicotinamide levels compared with other glomerulopathies. NMR-based metabonomic approach is amenable for the noninvasive diagnosis and differential diagnosis of FSGS as well as other glomerulopathies, and it could indicate the possible mechanisms of primary FSGS.
    PLoS ONE 11/2013; 8(11):e78531. DOI:10.1371/journal.pone.0078531 · 3.23 Impact Factor
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