Aberrantly glycosylated IgA1 induces mesangial cells to produce platelet-activating factor that mediates nephrin loss in cultured podocytes.
The reaction of mesangial cells with aberrantly glycosylated IgA1 has been implicated in the etiology of IgA nephropathy (IgAN). Tumor necrosis factor, which is assumed to mediate the interaction between mesangial cells and podocytes, also induces the expression of platelet-activating factor (PAF). In this study, we determined whether PAF affects the expression of nephrin (an adhesion molecule critical to glomerular permselectivity) and cytoskeletal F-actin organization in podocytes. We treated human mesangial cells with atypically glycosylated IgA1 either prepared in vitro or derived from the sera of patients with IgAN. We then prepared conditioned media from these cells and added them to cultured human podocytes in the presence of PAF receptor antagonists. Podocytes transfected to overexpress acetylhydrolase, the main catabolic enzyme of PAF, served as controls. Downregulation of nephrin expression and F-actin reorganization occurred when podocytes were cultured with mesangial cell-conditioned medium. Preincubation of podocytes with a PAF receptor antagonist prevented the loss and redistribution of nephrin. In control podocytes overexpressing acetylhydrolase, nephrin loss was abrogated. Our results suggest that atypically glycosylated IgA-induced PAF from mesangial cells is a mediator of podocyte changes, which, when more directly tested elsewhere, were found to be associated with proteinuria. Hence, it is possible that these in vitro findings may be relevant to the proteinuria of IgAN.
Coppo
Rosanna
R
Pediatric Nephrology, University of Turin, Regina Margherita Hospital, Turin, Italy. rosanna.coppo@unito.it
Fonsato
Valentina
V
Balegno
Sabrina
S
Ricotti
Emanuela
E
Loiacono
Elisa
E
Camilla
Roberta
R
Peruzzi
Licia
L
Amore
Alessandro
A
Bussolati
Benedetta
B
Camussi
Giovanni
G
D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D017077:Culture Media, Conditioned; D019084:Fluorescent Antibody Technique, Indirect; D006031:Glycosylation; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism*; D008565:Membrane Proteins / Q000502:physiology*; D050527:Mesangial Cells / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000235:genetics / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism*; D055815:Young Adult
D017077:Culture Media, Conditioned; D007070:Immunoglobulin A; D008565:Membrane Proteins; D010972:Platelet Activating Factor; C042441:glycosylated IgA; C113267:nephrin