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Podocyte and endothelial injury in focal segmental glomerulosclerosis: an ultrastructural analysis.

ABSTRACT: Podocyte injury contributes to the development of focal segmental glomerulosclerosis (FSGS). Endocapillary hypercellularity, which is one of the pathological characteristics of FSGS, suggests that glomerular endothelial injury may also be involved in the pathogenesis of FSGS. In electron micrographs of patients with FSGS (n = 43), we conducted morphometric measurements of foot process width (FPW) and podocyte detachment (PD) as markers of podocyte injury and subendothelial widening (SW) of the glomerular basement membrane as a marker of endothelial injury and compared them to those in patients with minimal change nephrotic syndrome (MCNS; n = 11) and control kidney donors (n = 5). Associations between ultrastructural and clinical parameters were analyzed according to the FSGS variants defined by the Columbia classification. FPW was significantly higher in the FSGS group than that in the MCNS and control groups, particularly in the collapsing, tip, and cellular variants of FSGS. Percentage of glomerular basement membrane (GBM) length showing PD and SW was significantly increased in the FSGS group, especially in the collapsing, cellular, and not otherwise specified variants. In FSGS, FPW was inversely correlated with disease duration, but not with proteinuria. Finally, the percentage of GBM length with SW significantly correlated with clinical parameters indicative of poor prognosis, such as lower remission rate and lower estimated glomerular filtration rate at the final observation. Quantitative measurement of podocyte and endothelial injury by electron microscopy might be useful for evaluating histological activity and predicting prognosis in FSGS.

SUBMITTER: Taneda S

PROVIDER: S-EPMC4609310 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Podocyte and endothelial injury in focal segmental glomerulosclerosis: an ultrastructural analysis.

Taneda Sekiko S Honda Kazuho K Ohno Mayuko M Uchida Keiko K Nitta Kosaku K Oda Hideaki H

Virchows Archiv : an international journal of pathology 20150813 4

Podocyte injury contributes to the development of focal segmental glomerulosclerosis (FSGS). Endocapillary hypercellularity, which is one of the pathological characteristics of FSGS, suggests that glomerular endothelial injury may also be involved in the pathogenesis of FSGS. In electron micrographs of patients with FSGS (n = 43), we conducted morphometric measurements of foot process width (FPW) and podocyte detachment (PD) as markers of podocyte injury and subendothelial widening (SW) of the g ...[more]

PMID: 26266776

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Project description:Background:Focal segmental glomerulosclerosis (FSGS) is a kidney disease that is commonly associated with proteinuria and the progressive loss of renal function, which is characterized by podocyte injury and the depletion and collapse of glomerular capillary segments. The pathogenesis of FSGS has not been completely elucidated; however, recent advances in molecular genetics have provided increasing evidence that podocyte structural and functional disruption is central to FSGS pathogenesis. Here, we identified a patient with FSGS and aimed to characterize the pathogenic gene and verify its mechanism. Methods:Using next-generation sequencing and Sanger sequencing, we screened the causative gene that was linked to FSGS in this study. The patient's total blood RNA was extracted to validate the messenger RNA (mRNA) expression of coenzyme Q10 monooxygenase 6 (COQ6) and validated it by immunohistochemistry. COQ6 knockdown in podocytes was performed in vitro with small interfering RNA, and then, F-actin was determined using immunofluorescence staining. Cell apoptosis was evaluated by flow cytometry, the expression of active caspase-3 was determined by Western blot, and mitochondrial function was detected by MitoSOX. Results:Using whole-exome sequencing and Sanger sequencing, we screened a new causative gene, COQ6, NM_182480: exon1: c.G41A: p.W14X. The mRNA expression of COQ6 in the proband showed decreased. Moreover, the expression of COQ6, which was validated by immunohistochemistry, also had the same change in the proband. Finally, we focused on the COQ6 gene to clarify the mechanism of podocyte injury. Flow cytometry showed significantly increased in apoptotic podocytes, and Western blotting showed increases in active caspase-3 in si-COQ6 podocytes. Meanwhile, reactive oxygen species (ROS) levels were increased and F-actin immunofluorescence was irregularly distributed in the si-COQ6 group. Conclusions:This study reported a possible mechanism for FSGS and suggested that a new mutation in COQ6, which could cause respiratory chain defect, increase the generation of ROS, destroy the podocyte cytoskeleton, and induce apoptosis. It provides basic theoretical basis for the screening of FSGS in the future.

Project description:Focal segmental glomerulosclerosis (FSGS) is a leading cause of kidney disease worldwide. The presumed etiology of primary FSGS is a plasma factor with responsiveness to immunosuppressive therapy and a risk of recurrence after kidney transplant-important disease characteristics. In contrast, adaptive FSGS is associated with excessive nephron workload due to increased body size, reduced nephron capacity, or single glomerular hyperfiltration associated with certain diseases. Additional etiologies are now recognized as drivers of FSGS: high-penetrance genetic FSGS due to mutations in one of nearly 40 genes, virus-associated FSGS, and medication-associated FSGS. Emerging data support the identification of a sixth category: APOL1 risk allele-associated FSGS in individuals with sub-Saharan ancestry. The classification of a particular patient with FSGS relies on integration of findings from clinical history, laboratory testing, kidney biopsy, and in some patients, genetic testing. The kidney biopsy can be helpful, with clues provided by features on light microscopy (e.g, glomerular size, histologic variant of FSGS, microcystic tubular changes, and tubular hypertrophy), immunofluorescence (e.g, to rule out other primary glomerulopathies), and electron microscopy (e.g., extent of podocyte foot process effacement, podocyte microvillous transformation, and tubuloreticular inclusions). A complete assessment of renal histology is important for establishing the parenchymal setting of segmental glomerulosclerosis, distinguishing FSGS associated with one of many other glomerular diseases from the clinical-pathologic syndrome of FSGS. Genetic testing is beneficial in particular clinical settings. Identifying the etiology of FSGS guides selection of therapy and provides prognostic insight. Much progress has been made in our understanding of FSGS, but important outstanding issues remain, including the identity of the plasma factor believed to be responsible for primary FSGS, the value of routine implementation of genetic testing, and the identification of more effective and less toxic therapeutic interventions for FSGS.

Dataset Information

Podocyte and endothelial injury in focal segmental glomerulosclerosis: an ultrastructural analysis.

Publications

Podocyte and endothelial injury in focal segmental glomerulosclerosis: an ultrastructural analysis.

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