Hyperactivation of WNT-β-Catenin and PI3K/Akt Pathways in Monocytes and B Lymphocytes of IgA Nephropathy (IgAN) Patients Could Lead to a Defect in Antigen Handling

A whole genomic screening was carried out to identify genes and pathways differently modulated in peripheral blood leukocytes isolated from 12 IgAN patients and 8 healthy subjects (HS). Bionformatic analysis revealed 210 genes discriminating IgAN pts from HS, these genes were also able to discriminate IgAN pts from other glomerular diseases. The identified set of genes generated highly significant networks involving WNT-b-catenin and PI3K/Akt. These pathways were further tested on peripheral blood mononuclear cells (PBMC) isolated from an independent group of 16 IgAN pts and 16 HS. Low protein levels of inversin and phosphatase and tensin homolog, two modulators of the WNT-b-catenin and PI3K/Akt pathways, were found in IgAN pts suggesting a hyperactivation of these pathways. Furthermore, we found increased phospho-Akt protein levels, nuclear b-catenin accumulation with enhanced PBMC proliferation in IgAN pts. Our next aim was to investigate which PBMC subpopulation of IgAN pts maybe principally involved in the WNT signaling alteration. We isolated T, B lymphocytes and monocytes and used a WNT pathway PCR Array to compare the transcript levels of 84 genes in IgAN pts and HS. Monocytes from IgAN pts showed an hyperactivation of the WNT pathway, in particular we found 24 significantly up regulated genes. B lymphocytes, showed a more blunt modulation since only 8 genes were found significantly up regulated, these genes overlapped with altered monocyte genes. T lymphocytes displayed only 5 deregulated genes. These findings highlight the emerging role of the WNT pathway in orchestrating the immune system in response to microbial stimulation of the immune cells in IgAN pts. Thus, the hyperactivation of this pathway could explain the abnormal systemic response to mucosal encountered antigens responsible for the onset of the disease. These newly identified pathways could be exploited for the identification of specific targets for the treatment