Urinary peptidomics analysis reveals proteases involved in diabetic nephropathy

Krochmal, M. et al. (2017) Urinary peptidomics analysis reveals proteases involved in diabetic nephropathy. Scientific Reports, 7, 15160. (doi: 10.1038/s41598-017-15359-9) (PMID:29123184) (PMCID:PMC5680307)

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Abstract

Mechanisms underlying the onset and progression of nephropathy in diabetic patients are not fully elucidated. Deregulation of proteolytic systems is a known path leading to disease manifestation, therefore we hypothesized that proteases aberrantly expressed in diabetic nephropathy (DN) may be involved in the generation of DN-associated peptides in urine. We compared urinary peptide profiles of DN patients (macroalbuminuric, n = 121) to diabetic patients with no evidence of DN (normoalbuminuric, n = 118). 302 sequenced, differentially expressed peptides (adjusted p-value < 0.05) were analysed with the Proteasix tool predicting proteases potentially involved in their generation. Activity change was estimated based on the change in abundance of the investigated peptides. Predictions were correlated with transcriptomics (Nephroseq) and relevant protein expression data from the literature. This analysis yielded seventeen proteases, including multiple forms of MMPs, cathepsin D and K, kallikrein 4 and proprotein convertases. The activity of MMP-2 and MMP-9, predicted to be decreased in DN, was investigated using zymography in a DN mouse model confirming the predictions. Collectively, this proof-of-concept study links urine peptidomics to molecular changes at the tissue level, building hypotheses for further investigation in DN and providing a workflow with potential applications to other diseases.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Delles, Professor Christian and Husi, Dr Holger and Mischak, Professor Harald
Authors: Krochmal, M., Kontostathi, G., Magalhães, P., Makridakis, M., Klein, J., Husi, H., Leierer, J., Mayer, G., Bascands, J.-L., Denis, C., Zoidakis, J., Zürbig, P., Delles, C., Schanstra, J. P., Mischak, H., and Vlahou, A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Scientific Reports
Publisher:Nature Publishing Group
ISSN:2045-2322
ISSN (Online):2045-2322
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Scientific Reports 7: 15160
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
669961RENALTRACTShireen DaviesEuropean Commission (EC)642937RI MOLECULAR CELL & SYSTEMS BIOLOGY