scholarly journals Degree of foot process effacement in patients with genetic focal segmental glomerulosclerosis: a single-center analysis and review of the literature

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kiyonobu Ishizuka ◽  
Kenichiro Miura ◽  
Taeko Hashimoto ◽  
Naoto Kaneko ◽  
Yutaka Harita ◽  
...  
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Cytoskeletal Proteins ◽  
Systematic Evaluation ◽  
Review Of The Literature ◽  
Segmental Glomerulosclerosis ◽  
Native Kidney ◽  
Foot Process Effacement ◽  
Genes Encoding ◽  
Foot Process ◽  
Almost All

AbstractDetermining the cause of focal segmental glomerulosclerosis (FSGS) has crucial implications for evaluating the risk of posttransplant recurrence. The degree of foot process effacement (FPE) on electron micrographs (EM) of native kidney biopsies can reportedly differentiate primary FSGS from secondary FSGS. However, no systematic evaluation of FPE in genetic FSGS has been performed. In this study, percentage of FPE and foot process width (FPW) in native kidney biopsies were analyzed in eight genetic FSGS patients and nine primary FSGS patients. All genetic FSGS patients showed segmental FPE up to 38% and FPW below 2000 nm, while all primary FSGS patients showed diffuse FPE above 88% and FPW above 3000 nm. We reviewed the literature which described the degree of FPE in genetic FSGS patients and identified 38 patients with a description of the degree of FPE. The degree of FPE in patients with mutations in the genes encoding proteins associated with slit diaphragm and cytoskeletal proteins was varied, while almost all patients with mutations in other FSGS genes showed segmental FPE. In conclusion, the present study suggests that the degree of FPE in native kidney biopsies may be useful for differentiating some genetic FSGS patients from primary FSGS patients.

scholarly journals Podocyte foot process effacement as a diagnostic tool in focal segmental glomerulosclerosis

2008 ◽  
Vol 74 (12) ◽  
pp. 1568-1576 ◽  
Author(s):  
Jeroen K.J. Deegens ◽  
Henry B.P.M. Dijkman ◽  
George F. Borm ◽  
Eric J. Steenbergen ◽  
José G. van den Berg ◽  
...  
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Diagnostic Tool ◽  
Segmental Glomerulosclerosis ◽  
Foot Process Effacement ◽  
Foot Process

scholarly journals Mechanical challenges and cytoskeletal impairments in focal segmental glomerulosclerosis

2018 ◽  
Vol 314 (5) ◽  
pp. F921-F925 ◽  
Author(s):  
Di Feng ◽  
Clark DuMontier ◽  
Martin R. Pollak
Keyword(s):  
Blood Flow ◽  
Focal Segmental Glomerulosclerosis ◽  
Kidney Injury ◽  
Future Research ◽  
Disease States ◽  
Filtration Barrier ◽  
Segmental Glomerulosclerosis ◽  
The Face ◽  
Foot Process ◽  
Future Research Directions

Focal segmental glomerulosclerosis (FSGS) is a histologically defined form of kidney injury typically mediated by podocyte dysfunction. Podocytes rely on their intricate actin-based cytoskeleton to maintain the glomerular filtration barrier in the face of mechanical challenges resulting from pulsatile blood flow and filtration of this blood flow. This review summarizes the mechanical challenges faced by podocytes in the form of stretch and shear stress, both of which may play a role in the progression of podocyte dysfunction and detachment. It also reviews how podocytes respond to these mechanical challenges in dynamic fashion through rearranging their cytoskeleton, triggering various biochemical pathways, and, in some disease states, altering their morphology in the form of foot process effacement. Furthermore, this review highlights the growing body of evidence identifying several mutations of important cytoskeleton proteins as causes of FSGS. Lastly, it synthesizes the above evidence to show that a better understanding of how these mutations leave podocytes vulnerable to the mechanical challenges they face is essential to better understanding the mechanisms by which they lead to disease. The review concludes with future research directions to fill this gap and some novel techniques with which to pursue these directions.

scholarly journals Proteolytic program-dependent functions are impaired in INF2-mediated focal segmental glomerulosclerosis

2019 ◽  
Author(s):  
Balajikarthick Subramanian ◽  
Justin Chun ◽  
Chandra Perez ◽  
Paul Yan ◽  
Isaac Stillman ◽  
...  
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Segmental Glomerulosclerosis ◽  
Terminal Fragment ◽  
Cathepsin Proteases ◽  
Foot Process ◽  
Inhibitory Domain ◽  
Altered Regulation ◽  
Actin Regulatory Proteins ◽  
And Function ◽  
Mutant Polypeptides

AbstractRegulation of the actin cytoskeleton is critical for normal glomerular podocyte structure and function. Altered regulation of the podocyte cytoskeleton can lead to proteinuria, reduced kidney filtration function and focal segmental glomerulosclerosis (FSGS). Mutations in inverted formin 2 (INF2), a member of the formin family of actin regulatory proteins, are the most common cause of autosomal dominant FSGS. INF2 is a multi-domain protein regulated by interaction between its N-terminal Diaphanous Inhibitory Domain (DID) and its C-terminal Diaphanous Auto-regulatory Domain (DAD). Although many aspects of the INF2 DID-DAD interaction are understood, it remains unclear why disease-causing mutations are restricted to the DID and how these mutations cause human disease. Here we report a proteolytic cleavage in INF2 that liberates the INF2 N-terminal DID to function independently of the INF2 C-terminal fragment containing the DAD domain. N-terminal DID region epitopes are differentially localized to podocyte foot process structures in normal glomeruli. This N-terminal fragment localization is lost in INF2-mediated FSGS, whereas INF2 C-terminal fragment epitopes localize to the podocyte cell body in both normal and disease conditions. INF2 cleavage is mediated by cathepsin proteases. In cultured podocytes, the wild-type INF2 N-terminal fragment localizes to membrane regions and promotes cell spreading, while these functions are impaired in a disease-associated INF2 mutant R218Q in the DID. These features are dependent on INF2-cleavage, with accompanying interaction of INF2 N-fragment with mDIA1. Our data suggest a unique cellular function of the DID dependent on INF2 cleavage and help explain the altered localization of FSGS-associated INF2 mutant polypeptides.

Podocyte alpha-actinin induction precedes foot process effacement in experimental nephrotic syndrome

1997 ◽  
Vol 273 (1) ◽  
pp. F150-F157 ◽  
Author(s):  
W. E. Smoyer ◽  
P. Mundel ◽  
A. Gupta ◽  
M. J. Welsh
Keyword(s):  
Nephrotic Syndrome ◽  
Cytoskeletal Proteins ◽  
Pathogenic Role ◽  
Puromycin Aminonucleoside ◽  
Altered Expression ◽  
Foot Process Effacement ◽  
Beta 1 Integrin ◽  
Foot Process ◽  
Actin Expression ◽  
Time Point

Attachment of podocytes to the glomerular basement membrane is thought to be mediated primarily by alpha 3/beta 1-integrins and by cytoskeletal proteins including actin, talin, vinculin, and alpha-actinin. We analyzed the expression of those molecules in rat glomeruli at several time points during induction of podocyte foot process effacement and nephrotic syndrome with puromycin aminonucleoside (PAN). PAN injection resulted in marked induction of glomerular alpha-actinin (40% increase vs. paired controls, P < 0.01), which clearly preceded development of podocyte foot process effacement and proteinuria and localized almost exclusively to podocytes. Delayed induction of glomerular alpha 3-integrin (44% increase vs. paired controls, P < 0.01) following foot process effacement was also observed but was not restricted to podocytes. No significant changes in glomerular vinculin, talin, beta 1-integrin, or total actin expression occurred at any time point during disease development. We conclude that foot process effacement is preceded by induction of alpha-actinin in podocytes in experimental nephrotic syndrome. Altered expression of this actin cross-linking protein in podocytes may have a pathogenic role in foot process effacement in nephrotic syndrome.

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