Contribution of the Endothelium to the Glomerular Permselectivity Barrier in Health and Disease

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Abstract

Background: The endothelium that lines glomerular capillaries shares many properties with endothelial cells in general, but unlike most endothelial cells, it is extremely flat and densely perforated by transendothelial cell pores, the fenestrae. Until recently, it was believed that the fenestrae allow free passage of large proteins, and that the glomerular endothelium contributes little to the permselectivity of the glomerular capillary wall. Methods: Key studies addressing the nature of the glomerular capillary endothelium and its contribution to glomerular permselectivity were reviewed. Results: Glomerular endothelial cell flattening and fenestrae formation requires signals from differentiated podocytes, and from the glomerular basement membrane. Deletion of VEGF-A from podocytes prevents flattening and fenestration of glomerular endothelium. Application of VEGF-A to endothelial cells in vivo stimulates fenestrae formation, and neutralization of VEGF-A by soluble VEGF receptor 1 (sFlt-1) or anti-VEGF antibodies results in loss of glomerular fenestrae, and proteinuria. Neutralizing TGF-β1 antibodies, deletion of laminin α3 in mice or laminin β3 in humans cause similar defects. The glomerular endotheliosis lesion of pre-eclampsia is due to the placenta-derived inhibitors sFlt-1 and sEndoglin, which block the VEGF-A/VEGF receptor and TGF-β/endoglin signaling, respectively, causing the loss of glomerular endothelial cell fenestrae, cell swelling and proteinuria. The glomerular endothelium is covered by a glycocalyx that extends into the fenestrae and by a more loosely associated endothelial cell surface layer of glycoproteins. Mathematical analyses of functional permselectivity studies have concluded that the glomerular endothelial cell glycocalyx and its associated surface layer account for the retention of up to 95% of proteins within the circulation. Furthermore, the fenestrae are critical for the maintenance of the high hydraulic conductivity of the glomerular capillary wall, and their loss results in a reduction in the glomerular filtration rate. Conclusions: Loss of GFR and proteinuria can result from glomerular endothelial cell injury.

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Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies.

Charles Jennette, Peter Heeringa, Adrian Schreiber … (2006)

Clinical and experimental data indicate that anti-neutrophil cytoplasmic autoantibodies (ANCAs) cause glomerulonephritis and vasculitis. Here we report the first evidence that complement is an important mediator of ANCA disease. Transfer of anti-myeloperoxidase (MPO) IgG into wild-type mice or anti-MPO splenocytes into immune-deficient mice caused crescentic glomerulonephritis that could be completely blocked by complement depletion. The role of specific complement activation pathways was investigated using mice with knockout of the common pathway component C5, classic and lectin binding pathway component C4, and alternative pathway component factor B. After injection of anti-MPO IgG, C4-/- mice developed disease comparable with wild-type disease; however, C5-/- and factor B-/- mice developed no disease. To substantiate a role for complement in human ANCA disease, IgG was isolated from patients with myeloperoxidase ANCA (MPO-ANCA) or proteinase 3 ANCA (PR3-ANCA) and from controls. Incubation of MPO-ANCA or PR3-ANCA IgG with human neutrophils caused release of factors that activated complement. IgG from healthy controls did not produce this effect. The findings suggest that stimulation of neutrophils by ANCA causes release of factors that activate complement via the alternative pathway, thus initiating an inflammatory amplification loop that mediates the severe necrotizing inflammation of ANCA disease.

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Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria.

Dominic Cosgrove, Akulapalli Sudhakar, David Charytan … (2003)

There are about 2.5 million glomeruli in the kidneys each consisting of a barrel of glomerular basement membrane surrounded by glomerular endothelial cells on the inside and glomerular epithelial cells with established foot processes (podocytes) on the outside. Defects in this filtration apparatus lead to glomerular vascular leak or proteinuria. The role of vascular endothelial growth factor (VEGF) in the regulation of glomerular vascular permeability is still unclear. Recent studies indicate that patients receiving anti-VEGF antibody therapy may have an increased incidence of proteinuria. In a different setting, pregnancies complicated by preeclampsia are associated with elevated soluble VEGF receptor 1 protein (sFlt-1), endothelial cell dysfunction and proteinuria. These studies suggest that neutralization of physiologic levels of VEGF, a key endothelial survival factor, may lead to proteinuria. In the present study, we evaluated the potential of anti-VEGF neutralizing antibodies and sFlt-1 in the induction of proteinuria. Our studies demonstrate that anti-VEGF antibodies and sFlt-1 cause rapid glomerular endothelial cell detachment and hypertrophy, in association with down-regulation of nephrin, a key epithelial protein in the glomerular filtration apparatus. These studies suggest that down-regulation or neutralization of circulating VEGF may play an important role in the induction of proteinuria in various kidney diseases, some forms of cancer therapy and also in women with preeclampsia.

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Spatial and temporal dynamics of the endothelium.

W Aird (2005)

The endothelium is a highly metabolically active organ that is involved in many physiological processes, including the control of vasomotor tone, barrier function, leukocyte adhesion and trafficking, inflammation, and hemostasis. Endothelial cell phenotypes are differentially regulated in space and time. Endothelial cell heterogeneity has important implications for developing strategies in basic research, diagnostics and therapeutics. The goals of this review are to: (i) consider mechanisms of endothelial cell heterogeneity; (ii) discuss the bench-to-bedside gap in endothelial biomedicine; (iii) revisit definitions for endothelial cell activation and dysfunction; and (iv) propose new goals in diagnosis and therapy. Finally, these themes will be applied to an understanding of vascular bed-specific hemostasis.

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Author and article information

Journal

Journal ID (publisher-id): NEP

Journal ID (nlm-ta): Nephron Physiol

Journal ID (doi): 10.1159/issn.1660-2137

Title: Nephron Physiology

Publisher: S. Karger AG

ISBN: 978-3-8055-8311-4

ISBN: 978-3-318-01479-2

ISSN (Electronic): 1660-2137

Publication date Subscription-year: 2007

Publication date (Print): June 2007

Publication date (Electronic): 06 June 2007

Volume: 106

Issue: 2

Pages: p19-p25

Affiliations

University of Alberta, Edmonton, Alta., Canada

Article

Publisher ID: 101796 Other ID: Nephron Physiol 2007;106:p19–p25

DOI: 10.1159/000101796

PubMed ID: 17570944

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