Aberrantly glycosylated IgA1 induces mesangial cells to produce platelet-activating factor that mediates nephrin loss in cultured podocytes

Abstract

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.

Spleen Tyrosine Kinase Is Important in the Production of Proinflammatory Cytokines and Cell Proliferation in Human Mesangial Cells following Stimulation with IgA1 Isolated from IgA Nephropathy Patients

“…Mesangial cell-derived mediators induce proliferation of proximal tubular epithelial cells and synthesis of inflammatory mediators (29). Moreover, mesangial cell-derived TNF-a and plateletactivating factor downregulate podocyte markers, resulting in altered glomerular permeability and enhanced proteinuria in IgAN (30,31). These data indicate that such mediators play an important role in the cross-talk between the different cell types present in glomeruli.…”

Lipidomics

“…Recently the molecular distribution of lipids was analyzed in hyper-IgA murine kidneys using MALDI-quadrupole ion trap-TOF-based imaging MS [133]. [134,135]. This study also indicated that all the hyper-IgA-specific lipids were derived from urine and that stagnation due to unilateral urethral obstruction caused hyper-IgA-specific distribution of lipids in renal tubules.…”

Autoantibodies Targeting Galactose-Deficient IgA1 Associate with Progression of IgA Nephropathy

“…Based on the physical and biologic characteristics of the immune complexes, such as composition and size, 17,28 mesangial cells may be activated to proliferate and overproduce components of mesangial matrix, chemokines, and cytokines. 29,30 Overall, the serum levels of normalized IgG autoantibody and total IgA autoantibody steadily increased with the ARR level (ARR=3 . ARR=2 .…”