Thrombospondin Type 1 Domain–Containing 7A Localizes to the Slit Diaphragm and Stabilizes Membrane Dynamics of Fully Differentiated Podocytes

Abstract

BackgroundAbout 3%–5% of adults with membranous nephropathy have autoantibodies directed against thrombospondin type 1 domain–containing 7A (THSD7A), a podocyte-expressed transmembrane protein. However, the temporal and spatial expression of THSD7A and its biologic function for podocytes are unknown, information that is needed to understand the effects of THSD7A autoantibodies in this disease.MethodsUsing a variety of microscopic techniques, we analyzed THSD7A localization in postnatal, adult, and autoantibody-injected mice as well as in human podocytes. We also analyzed THSD7A function in human podocytes using confocal microscopy; Western blotting; and adhesion and migration assays.ResultsWe found that THSD7A expression begins on glomerular vascularization with slit diaphragm formation in development. THSD7A localizes to the basal aspect of foot processes, closely following the meanders of the slit diaphragm in human and mice. Autoantibodies binding to THSD7A localize to the slit diaphragm. In human podocytes, THSD7A expression is accentuated at filopodia and thin arborized protrusions, an expression pattern associated with decreased membrane activity of cytoskeletal regulators. We also found that, phenotypically, THSD7A expression in human podocytes is associated not only with increases in cell size, enhanced adhesion, and reduced detachment from collagen type IV–coated plates but also, with decreased ability to migrate.ConclusionsOur findings suggest that THSD7A functions as a foot process protein involved in the stabilization of the slit diaphragm of mature podocytes and that autoantibodies to THSD7A, on the basis of their localization, might structurally and functionally alter the slit diaphragm’s permeability to protein.

Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy

“…NELL-1-associated MN appears to be unique kidney disease associated with overexpression of NELL-1. As is the case for PLA2R and THSD7A, 22 anti-NELL-1 antibodies recognize a conformation-dependent epitope (found both in 280-kDa homodimers and 420-kDa homotrimers formed through a helical coiled-coil domain). Further studies are needed to determine NELL-1 ultrastructural localization at the podocyte and the potential role of anti-NELL-1 antibodies in podocyte adhesion and slit diaphragm stabilization.…”

The Evolving Role of Novel Biomarkers in Glomerular Disease: A Review

“…54 THSD7A localizes to the slit diaphragm of podocyte foot processes and is associated with enhanced stabilization of the slit diaphragm in cultured podocytes, supporting a pathogenic role. 62 The positivity rate of antibody in serum and tissue is highly correlated. 55 Serum IIF has 92% diagnostic sensitivity and 100% specificity.…”

Idiopathic Membranous Nephropathy: Glomerular Pathological Pattern Caused by Extrarenal Immunity Activity

“…This finding may suggest that the location of auto-antigenic proteins may determine their ability to cause damage to podocytes. Recently, using a variety of microscopes, it was found that THSD7A localizes at the basal aspect of foot processes, closely following the meanders of the slit diaphragm in human and mice, and the anti-THSD7A antibodies bind THSD7A expressed on the slit diaphragm ( 64 ). In human podocytes, THSD7A expression is accentuated at filopodia and thin arborized protrusions, an expression pattern associated with the decreased membrane activity of cytoskeletal regulators.…”

“…In human podocytes, THSD7A expression is accentuated at filopodia and thin arborized protrusions, an expression pattern associated with the decreased membrane activity of cytoskeletal regulators. Phenotypically, THSD7A expression in human podocytes is associated with an increase in cell size and enhanced adhesion to collagen type IV-coated plates ( 64 ). Again, due to the lack of evidence on the precise localization of PLA2R1, it is currently reasonable to believe in renal pathology that PLA2R1 could also express at the basal domain or slit diaphragm of podocytes and can disrupt the function of podocytes, such as their adhesion ability to collagen type IV (GBM) ( 65 ).…”