IgA1 deposition may induce NLRP3 expression and macrophage transdifferentiation of podocyte in IgA nephropathy

Abstract

BackgroundThe NLRP3 inflammasome plays an important role in mediating podocyte injury in various kidney diseases. The aim of this study was to investigate whether NLRP3 expression associated with podocyte injury was involved in the pathogenesis of IgA nephropathy (IgAN).MethodsNLRP3 inflammasomes and macrophage marker (F4/80) were detected in the renal tissues of IgAN patients. Association between kidney NLRP3 levels and the clinical feature of IgAN patients was analyzed. Podocytes were incubated with serum containing dys-glycosylated IgA1 protein isolated from IgAN patients. Expression of NLRP3 inflammasomes, F4/80, inflammatory cytokine and renal fibrosis marker were measured using RT-PCR and Western blotting.ResultsRenal NLRP3 inflammasome expression was significantly increased in IgAN patients compared to normal control tissues. Moreover, co-expression of NLRP3 and F4/80 could be observed in the podocytes of IgAN patients. Patients with eGFR < 60 ml/min/1.73 m2 had remarkably higher tubular NLRP3 expression (P < 0.05), while patients with gross proteinuria (≥ 3.5 g/day) had a significantly higher glomerular NLRP3 expression (P < 0.05). Further analysis indicated that dys-glycosylated IgA1 isolated from IgAN patient serum could induce podocyte expression of NLRP3 and the macrophage marker F4/80, which could lead to induction of an inflammatory reaction (increased expression of ICAM-1) and fibrosis (increased expression of α-SMA).ConclusionDys-glycosylated IgA1 isolated from IgAN patient serum could induce NLRP3 expression in podocytes and initiate podocyte macrophage transdifferentiation (PMT). After PMT, podocytes secrete proinflammatory cytokines that can contribute to the inflammation cascade and renal fibrosis changes associated with IgAN.

Lower serum bilirubin is associated with poor renal outcome in IgA nephropathy patients

“…Besides, it is reported that bilirubin interferes with vascular cell adhesion molecule1 (VCAM-1) and intercellular adhesion molecule1 (ICAM-1) to regulate atherosclerotic lesion formation and vascular inflammation both in animal and human models [9,24]. Furthermore, bilirubin participates in immune response at several levels including modulation of regulatory T cells and T helper type 17 (Th17) cells, inhibition of the Toll-like receptor 4/nuclear factor kappaB signaling pathway, down-regulation of NLRP3 inflammasome [8,[24][25][26], which has been proved to be very important for IgA nephropathy in a previous study by our team [27].…”

Lower serum bilirubin is associated with poor renal outcome in IgA nephropathy patients: A retrospective study

“…Besides, it is reported that bilirubin interferes with vascular cell adhesion molecule1 (VCAM-1) and intercellular adhesion molecule1 (ICAM-1) to regulate atherosclerotic lesion formation and vascular in ammation both in animal and human models [9,24]. Furthermore, bilirubin participates in immune response at several levels including modulation of regulatory T cells and T helper type 17 (Th17) cells, inhibition of the Toll-like receptor 4/nuclear factor kappaB signaling pathway, down-regulation of NLRP3 in ammasome [8,[24][25][26], which has been proved to be very important for IgA nephropathy in a previous study by our team [27].…”

Case Report: Silicosis and IgA nephropathy, an exceptional association

“…In fact, NLRP3 are the key in the inflammatory process caused by silica: they are involved, in association with alveolar macrophages, in binding and eliminating crystalline silica particles, and thus leading to pulmonary fibrosis in recent studies. 3,14 The real mechanism and pathophysiology are still not fully elucidated and needs more study to further understand how silica leads to autoimmunity and glomerulonephritis. In our case, simultaneous kidney and pulmonary disease could suggest the hypothesis that Ig A nephropathy might be associated with silica exposure.…”