Molecular bases of rare and inherited kidney diseases: From insult to repair

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During the past five years, our research projects were focused on the pathomechanisms of membranous nephropathy (MN), a rare (auto-) immune disease affecting the podocyte, to which our team (H.Debiec) has made major contributions, and of a novel systemic disease caused by mutations in the alpha1 chain of type IV collagen (COL4A1), that we called HANAC (Hereditary Angiopathy with Nephropathy, Aneurysms and Cramps), (Emmanuelle.Plaisier). We have identified the first food antigen, cationic bovine serum albumin (cBSA), implicated in immune glomerulopathies and two series of high-risk alleles of the immune response gene HLA-DQA1 and the PLA2R1 gene encoding the receptor for phospholipase A2 involved in MN.

In addition, we have pursued our line of study on the role of matrix metalloproteases (MMP) in renal diseases with a special attention to inherited diseases. We have identified new roles of MMP9 in nephron formation, in cystogenesis, and as an anti-apoptotic factor via the release of SCF (Brigitte Lelongt), and we have further characterized the effects of its splice variant MMP9-DEx2 (R.Piedagnel). Part of the studies on matrix remodelling, particularly those on mediators of fibrosis, has been performed in close collaboration with Team 2 (J.J. Boffa).

We will develop/use new technological approaches such as HLA peptidomics and next generation sequencing techniques: i) to unravel the pathogenic epitopes triggering immune response and the genetics of MN by sequencing HLA-D and PLA2R1 loci and potentially predisposing genes, ii) to identify new gene mutations in HANAC-related disorders and to understand the pathomechanisms of vascular, renal and muscular involvement in knockin mice, as well as the contribution of abnormal basement membrane to cystogenesis, iii) to characterize modifying genes that can reverse a cystic phenotype in revertant PKD mice that we have generated. We will further investigate the role of MMP9 and its splice variant in the cystogenetic process, and participate in a transversal programme aimed at deciphering epigenetic regulation events, particularly the role of histone acetylation in kidney disease progression and repair. Our ultimate goal is to identify druggable molecular targets and to set up new diagnostic assays.​