Upregulation of the immunoproteasome in peripheral blood mononuclear cells of patients with IgA nephropathy

Abstract

In order to present an antigen to T-cells, the antigen must first be degraded by proteasomes. Following exposure to interferons, some proteasome subunits (ss1,ss2,ss5) are replaced by others (LMP2, LMP7, MECL-1) that have more optimal catalytic properties for peptide presentation; this more efficient organelle is termed the immuno-proteasome. Here we measured gene expression of various subunits in peripheral mononuclear cells of patients with IgA nephropathy, a disease with features of immune dysregulation. We used quantitative PCR to measure the expression of proteasomal subunit mRNA in mononuclear cells from IgA nephropathy patients, a group of proteinuric control patients with idiopathic nephrotic syndromes, and healthy controls. A significant switch in the expression of trypsin- and chymotrypsin-like proteasome subunits to corresponding immuno-proteasome subunits was found in patients as compared to healthy controls. Further, we found that nuclear translocation of NF-kappaB p50 and p65 was significantly greater in the IgA nephropathy patients, but this did not correlate with the switch to the immuno-proteasome phenotype. Patients with proteinuria greater than 0.5 g/1.73 m(2)/day had a significant switch of the chymotryptic-like beta5 protease to the LMP7 subunit, but this did not occur in patients with idiopathic nephrotic syndrome. The switch to an immuno-proteasome in peripheral blood mononuclear cells of patients with IgA nephropathy suggests an increased efficiency of antigen processing and presentation. This switch appears to be independent of a coincidental activation of the NF-kappaB pathway but is associated with high levels of proteinuria, a well known risk factor for progression of IgA nephropathy.

Oxidative Stress and Galactose-Deficient IgA1 as Markers of Progression in IgA Nephropathy

“…Aberrantly glycosylated IgA1 can activate transcription factor NF-B in mononuclear cells (7). We recently reported increased NF-B nuclear translocation in peripheral blood mononuclear cells of patients with IgAN, particularly during phases of clinical activity (36). AOPPs can activate NF-B also in mesangial cells (31).…”

MicroRNA‑520a suppresses the proliferation and mitosis of HaCaT cells by inactivating protein kinase B

“…The phosphatidylinositol 3-kinase (PI3K)/AKT pathway has recently been identified to be associated with psoriasis (17). AKT was predicted as the target gene of miR-520a in the present study and AKT may serve a crucial role in the proliferation of HaCaT cells.…”

IgA Nephropathy: Insights into Genetic Basis and Treatment Options

“…Low gene expression of inversion and phosphatase and tensin homolog (PTEN) are responsible for the hyperactivation of these two pathways that enhance cell proliferation through lymphoid enhancer factor-1 (LEF-1) of which the gene is located within our previous described region 4q26-31 linked to IgAN [Bisceglia et al, 2006]. Finally, the hyperactivation of the PJ3k/Akt pathway is in linkage with the upregulation of the immunoproteasome in peripheral blood mononuclear cells of IgAN patients, reported by Coppo et al, [2009]. Expression profiling using serial analysis of gene expression (SAGE) and microarray techniques allows global description of expressed genes present in renal tissue.…”