Decreased Podocyte Vesicle Transcytosis and Albuminuria in APC C-Terminal Deficiency Mice with Puromycin-Induced Nephrotic Syndrome

In minimal change nephrotic syndrome, podocyte vesicle transport is enhanced. Adenomatous polyposis coli (APC) anchors microtubules to cell membranes and plays an important role in vesicle transport. To clarify the role of APC in vesicle transport in podocytes, nephrotic syndrome was induced by puromycin amino nucleoside (PAN) injection in mice expressing APC1638T lacking the C-terminal of microtubule-binding site (APC1638T mouse); this was examined in renal tissue changes. The kidney size and glomerular area of APC1638T mice were reduced (p = 0.014); however, the number of podocytes was same between wild-type (WT) mice and APC1638T mice. The ultrastructure of podocyte foot process was normal by electron microscopy. When nephrotic syndrome was induced, the kidneys of WT+PAN mice became swollen with many hyaline casts, whereas these changes were inhibited in the kidneys of APC1638T+PAN mice. Electron microscopy showed foot process effacement in both groups; however, APC1638T+PAN mice had fewer vesicles in the basal area of podocytes than WT+PAN mice. Cytoplasmic dynein-1, a motor protein for vesicle transport, and α-tubulin were significantly reduced in APC1638T+PAN mice associated with suppressed urinary albumin excretion compared to WT+PAN mice. In conclusion, APC1638T mice showed reduced albuminuria associated with suppressed podocyte vesicle transport when minimal change nephrotic syndrome was induced.

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Mechanism Underlying Selective Albuminuria in Minimal Change Nephrotic Syndrome

International Journal of Nephrology ◽

10.1155/2019/5859102 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8

Author(s):

Akihiro Tojo

Keyword(s):

Nephrotic Syndrome ◽

A Priori ◽

Minimal Change Nephrotic Syndrome ◽

Cytoplasmic Dynein ◽

Minimal Change ◽

Filtration Barrier ◽

Urinary Protein Level ◽

Foot Process ◽

Albumin Receptor ◽

Albumin Endocytosis

As water and solutes are filtered through the slit membrane, it is an a priori concept that a slit membrane is an essential filtration barrier for proteins, including albumin. However, in cases of minimal change nephrotic syndrome, the number of slit membranes is reduced by the foot process effacement and tight junction-like cell adhesion. Furthermore, albumin endocytosis is enhanced in the podocytes under condition of minimal change disease, and albumin is selectively transported by the albumin receptor FcRn. Suppressing the endocytosis of albumin with anti-FcRn antibody decreases the urinary protein level. The expression of motor molecules, such as cytoplasmic dynein 1 and myosin IX, is increased in the podocytes under conditions of minimal change nephrotic syndrome, suggesting the enhanced transport of vesicles containing albumin. Podocyte vesicle transport may play an important role in the pathology of selective albuminuria in cases of nephrotic syndrome.

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P0338CRUMBS HOMOLOG2-EZRIN SIGNALING INDUCED PODOCYTE INJURY, LEADING TO MINIMAL-CHANGE DISEASE(MCD) AND FOCAL SEGMENTAL GLOMERULOSCLEROSIS(FSGS)

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa144.p0338 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Ichiro Hada

Keyword(s):

Electron Microscopy ◽

Nephrotic Syndrome ◽

Cell Line ◽

Focal Segmental Glomerulosclerosis ◽

Minimal Change Disease ◽

Immunofluorescence Microscopy ◽

Minimal Change ◽

Podocyte Injury ◽

Heavy Proteinuria ◽

Foot Process

Abstract Background and Aims The etiology and cellular pathogenesis of podocyte injury leading to minimal-change disease (MCD) and focal segmental glomerulosclerosis (FSGS) remain largely obscure. Genetic mutation of crumbs homolog 2 (CRB2) is a cause of congenital nephrotic syndrome. Type-1 transmembrane proteins including CRB2 transduce outside-in signals that are involved in various cellular events including changes in the cytoskeletal network. The aim of the present study is to determine whether alteration of CRB2-mediated signaling in podocytes causes MCD and FSGS. Method Mice were immunized with a partial recombinant protein including the extracellular part of mouse CRB2. Urinalysis was obtained, and the kidney was subjected to histopathology. Kidney samples were also subjected to immunofluorescence microscopy and glomerular isolation to determine whether activation of the ezrin/radixin/moesin (ERM) family of cross-linkers between plasma membrane proteins and the actin cytoskeleton is involved in the pathogenesis of this nephrotic model. A CRB2-expressing mouse podocyte cell line was generated and incubated with anti-CRB2 antibody, and cell lysates were subjected to immunoblot analysis of ERM phosphorylation. The presence of anti-CRB2 antibody in the serum was determined by Western blot analysis. Results Apparent anti-CRB2 antibody was detected in the serum from 4 weeks onward. Immunized mice developed proteinuria at 4 weeks, which continued at least until 29 weeks. Mice developing extremely heavy proteinuria also developed hematuria from 18 weeks onward. Light microscopy revealed MCD in mice with proteinuria alone and FSGS in mice with heavy proteinuria and hematuria. Immunofluorescence microscopy revealed positive granular IgG staining in podocyte foot processes, but not complement C3. Electron microscopy and immuno-electron microscopy revealed alteration of actin organization associated with prominent foot process effacement. Strong phosphorylation of ezrin was observed in the glomerulus from the proteinuric stage and in the cellular lysates from the CRB2-expressing podocyte cell line incubated with anti-CRB2 antibody. Conclusion The current data revealed that binding of anti-CRB2 antibody to the extracellular domain of CRB2 on the podocyte foot process activated the ezrin-cytoskeleton network, leading to podocyte injury. Our data also indicated that signaling by this one molecular can induce two different phenotypes of glomerular injury: MCD and FSGS. In our model, the signaling was activated by anti-CRB2 antibody, but in patients with nephrotic syndrome the CRB2 ligands remain unknown. Therefore, it will be important to identify the soluble factors interacting with CRB2, which may be novel factors contributing to the pathogenesis of MCD and FSGS.

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Foot process fusion and glomerular filtration rate in minimal change nephrotic syndrome

Kidney International ◽

10.1038/ki.1984.76 ◽

1984 ◽

Vol 25 (4) ◽

pp. 696-700 ◽

Cited By ~ 44

Author(s):

Sven-Olof Bohman ◽

Georg Jaremko ◽

Ann-Britt Bohlin ◽

Ulla Berg

Keyword(s):

Nephrotic Syndrome ◽

Glomerular Filtration Rate ◽

Glomerular Filtration ◽

Filtration Rate ◽

Minimal Change Nephrotic Syndrome ◽

Minimal Change ◽

Foot Process

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Minimal-change nephropathy and focal segmental glomerulosclerosis

Oxford Textbook of Medicine ◽

10.1093/med/9780199204854.003.210803 ◽

2010 ◽

pp. 3978-3985

Author(s):

Dwomoa Adu

Keyword(s):

Electron Microscopy ◽

Nephrotic Syndrome ◽

Epithelial Cell ◽

Basement Membrane ◽

Light Microscopy ◽

Outer Surface ◽

Minimal Change Nephrotic Syndrome ◽

Minimal Change ◽

Immune Mediated ◽

Inflammatory Drugs

Minimal-change nephrotic syndrome (MCNS) is an immune-mediated condition, usually of unknown cause, but which can sometimes be associated with Hodgkin’s disease or the use of nonsteroidal anti-inflammatory drugs. On light microscopy the glomeruli appear normal or small, and on electron microscopy there is effacement of epithelial-cell foot processes over the outer surface of the glomerular basement membrane. MCNS is the cause of about 80% of cases of nephrotic syndrome in children and 20% in adults....

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Prognosis of Children With Nephrotic Syndrome

Pediatrics in Review ◽

10.1542/pir.12.5.132 ◽

1990 ◽

Vol 12 (5) ◽

pp. 132-148

Keyword(s):

Electron Microscopy ◽

Nephrotic Syndrome ◽

Membranoproliferative Glomerulonephritis ◽

Minimal Change Nephrotic Syndrome ◽

Minimal Change ◽

Age Difference ◽

Focal Glomerulosclerosis ◽

Mesangial Proliferation ◽

Collaborative Studies ◽

Modern Era

Well before the modern era of diagnosis and management of nephrotic syndrome (characterized by proteinuria, hypoalbuminemia, edema, and hypercholesterolemia), pediatricians recognized a different, more benign form of the disorder than did internists. This age difference has been borne out by the remarkable international collaborative studies in children's renal centers. With the advent of more precise renal biopsy diagnosis by thin section and electron microscopy, pathological diagnosis now includes minimal glomerular changes, focal glomerulosclerosis, mesangial proliferation, and mesangial proliferation with focal segmental glomerulosclerosis. Eighty percent of patients with primary nephrotic syndrome or minimal change nephrotic syndrome experience symptoms before 6 years of age, but membranoproliferative glomerulonephritis rarely appears before this age.

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Minimal change disease

Treatment of Primary Glomerulonephritis ◽

10.1093/med/9780198784081.003.0004 ◽

2019 ◽

pp. 175-224

Author(s):

Claudio Ponticelli ◽

Richard J Glassock ◽

Rosanna Coppo

Keyword(s):

Electron Microscopy ◽

Nephrotic Syndrome ◽

Light Microscopy ◽

Renal Biopsy ◽

Minimal Change Disease ◽

The Elderly ◽

Minimal Change ◽

Common Cause ◽

Foot Process

This chapter discusses minimal change disease (MCD), which is chiefly characterized clinically by episodes of nephrotic syndrome (NS) and presents with massive proteinuria, hypo-albuminaemia, hyperlipidaemia, and generalized oedema, Morphologically, it is characterized by no or only minimal glomerular abnormalities in a renal biopsy examined by light microscopy and immunofluorescence, while there is diffuse effacement of the podocyte foot process by electron microscopy. MCD is the most common cause of NS in children but it may also develop at any age, including in the elderly. This chapter covers the pathology, presentation, and treatment of MCD, including practical tips for the practitioner.

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