Unknown,Transcriptomics,Genomics,Proteomics

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The molecular phenotype of endocapillary proliferation in IgA nephropathy and potential modulation by bioactive small molecules

ABSTRACT: Endocapillary proliferation is associated with higher risk of progressive disease in IgAN. To better understand molecular pathways involved in the development of endocapillary proliferation and to identify novel specific therapeutic targets, we evaluated the glomerular transcriptome of microdissected kidney biopsies from 22 patients with IgAN. Endocapillary proliferation was defined according to the Oxford scoring system by 3 nephropathologists. We analyzed mRNA expression using microarrays and identified transcripts differentially expressed in patients with endocapillary proliferation. Next, we employed both transcription factor analysis and in silico drug screening and confirmed that the endocapillary proliferation transcriptome is significantly enriched with pathways modulated by corticosteroid exposure. With this approach we also identified novel therapeutic targets and bioactive small molecules that may be considered for therapeutic trials for treatment of IgAN. RNA from glomerular compartment was extracted and processed for hybridization on Affymetrix microarrays.

ORGANISM(S): Homo sapiens

SUBMITTER: Celine Berthier

PROVIDER: E-GEOD-50469 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

The molecular phenotype of endocapillary proliferation: novel therapeutic targets for IgA nephropathy.

Hodgin Jeffrey B JB Berthier Celine C CC John Rohan R Grone Elisabeth E Porubsky Stefan S Gröne Hermann-Josef HJ Herzenberg Andrew M AM Scholey James W JW Hladunewich Michelle M Cattran Daniel C DC Kretzler Matthias M Reich Heather N HN

PloS one 20140818 8

IgA nephropathy (IgAN) is a clinically and pathologically heterogeneous disease. Endocapillary proliferation is associated with higher risk of progressive disease, and clinical studies suggest that corticosteroids mitigate this risk. However, corticosteroids are associated with protean cellular effects and significant toxicity. Furthermore the precise mechanism by which they modulate kidney injury in IgAN is not well delineated. To better understand molecular pathways involved in the development ...[more]

PMID: 25133636

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Project description:The hallmark of IgA nephropathy (IgAN) is gross hematuria (GH) coinciding with or immediately following an upper respiratory or gastrointestinal tract infection and can represent the disease triggering event. Therefore, a whole genomic screening of IgAN patients during the GH was done to clarify the link between mucosal encountered antigens and the occurrence of glomerular hematuria. The modulated genes during GH show a clear involvement of the interferon signalling, antigen presenting pathway, and the immuno-proteasome. The gene characterizing cytotoxic effector lymphocytes (CX3CR1) implicated in vascular endothelial damage, was found up-regulated at both mRNA and protein level. In vitro antigenic stimulation of PBMCs on an independent set of IgAN patients and healthy blood donors (HBS) demonstrated that patients upregulate specifically CX3CR1 in an enhanced and dose dependant manner, while an expected down-regulation occurred in HBD. This enhanced activation occurred in both patients characterized by recurrent GH and by permanent microscopic hematuria (MH). We then analyzed glomerular fractalkine (FKN) expression, since this ligand is involved in the vascular gateway for CX3CR1+ cells towards the inflamed tissues. A significantly higher FKN expression on the capillary vessels and podocytes was found in recurrent GH patients compared to permanent MH, suggesting a predisposition for cytotoxic cell extravasation in recurrent GH patients. Taken together, our findings demonstrate, for the first time, a defect in antigen handling in PBMCs of IgAN patients with a specific up-regulation of CX3CR1. Furthermore, the constitutive up regulation of glomerular FKN, suggests an involvement of the CX3CR1-FKN axis in the exacerbation of GH. Gene expression profile comparison 3 IgAN patients at two different clinical time points, the first sample during the gross hematuria episode and the second during the remission phase of the disease characterized by microscopic hematuria

Dataset Information

The molecular phenotype of endocapillary proliferation in IgA nephropathy and potential modulation by bioactive small molecules

Publications

The molecular phenotype of endocapillary proliferation: novel therapeutic targets for IgA nephropathy.

Similar Datasets

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