Identification of novel molecular signatures of IgA nephropathy through an integrative -omics analysis

Abstract

IgA nephropathy (IgAN) is the most prevalent among primary glomerular diseases worldwide. Although our understanding of IgAN has advanced significantly, its underlying biology and potential drug targets are still unexplored. We investigated a combinatorial approach for the analysis of IgAN-relevant -omics data, aiming at identification of novel molecular signatures of the disease. Nine published urinary proteomics datasets were collected and the reported differentially expressed proteins in IgAN vs. healthy controls were integrated into known biological pathways. Proteins participating in these pathways were subjected to multi-step assessment, including investigation of IgAN transcriptomics datasets (Nephroseq database), their reported protein-protein interactions (STRING database), kidney tissue expression (Human Protein Atlas) and literature mining. Through this process, from an initial dataset of 232 proteins significantly associated with IgAN, 20 pathways were predicted, yielding 657 proteins for further analysis. Step-wise evaluation highlighted 20 proteins of possibly high relevance to IgAN and/or kidney disease. Experimental validation of 3 predicted relevant proteins, adenylyl cyclase-associated protein 1 (CAP1), SHC-transforming protein 1 (SHC1) and prolylcarboxypeptidase (PRCP) was performed by immunostaining of human kidney sections. Collectively, this study presents an integrative procedure for -omics data exploitation, giving rise to biologically relevant results.

How will artificial intelligence and bioinformatics change our understanding of IgA Nephropathy in the next decade?

“…More generic profiling of blood proteins and peptides can provide biomarkers and molecular signatures. One study analyzed nine published urinary proteomics datasets and integrated them with transcriptomic data and literature knowledge to identify twenty proteins involved in IgAN in the kidney [22]. The relevance of three of these proteins (adenylcyclase-associated protein 1 (CAP1), SHCtransforming protein 1 (SHC1), and prolylcarboxypeptidase (PRCP)) was experimentally confirmed [22].…”

“…One study analyzed nine published urinary proteomics datasets and integrated them with transcriptomic data and literature knowledge to identify twenty proteins involved in IgAN in the kidney [22]. The relevance of three of these proteins (adenylcyclase-associated protein 1 (CAP1), SHCtransforming protein 1 (SHC1), and prolylcarboxypeptidase (PRCP)) was experimentally confirmed [22]. Finally, proteomics, like transcriptomics, is becoming increasingly available with spatial resolution from tissues [12], paving the way to generate multiplexed-histological data to complement classic pathological assessment.…”

Value of Urine Peptides in Assessing Kidney and Cardiovascular Disease

“…Krochmal and colleagues compared urinary peptide profiles of patients with and without CKD ( n = 121 and n = 118). [ 71 ] 302 differentially expressed peptides (adjusted p < 0.05) were analyzed with Proteasix. Activity of the predicted proteases was estimated based on the change in abundance of the investigated peptides.…”

“…In a subsequent study Krochmal and colleagues employed similar approaches to identify proteases potentially relevant in IgA nephropathy. [ 71 ] Combining the results with data from other public repositories allowed identifying 20 highly significant pathways. From these, three proteins predicted to be functionally relevant, adenylyl cyclase‐associated protein 1, SHC‐transforming protein 1, and prolylcarboxypeptidase were further verified by immunohistochemistry.…”

Chronic kidney disease: a review of proteomic and metabolomic approaches to membranous glomerulonephritis, focal segmental glomerulosclerosis, and IgA nephropathy biomarkers

“…Among 232 proteins, 20 pathways were associated with IgAN consisting of 657 proteins for further analysis. They found 20 proteins with the highest relevance to disease pathology and finally validated 3 proteins which were the most important ones (including adenylyl cyclase-associated protein 1 [CAP1], prolylcarboxypeptidase [PRCP], and SHC-transforming protein 1 [SHC1]) by immunostaining of kidney tissue sections [108]. Gene ontology analysis showed that, a substantial part of significant proteins are involved in platelet activation processes, signaling and aggregation, which are all important in IgA pathology.…”