Urinary peptidomics analysis reveals proteases involved in diabetic nephropathy

Magda Krochmal, Georgia Kontostathi, Pedro Magalhães, Manousos Makridakis, Julie Klein, Holger Husi, Johannes Leierer, Gert Mayer, Jean-Loup Bascands, Colette Denis, Jerome Zoidakis, Petra Zürbig, Christian Delles, Joost P. Schanstra, Harald Mischak, Antonia Vlahou

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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.
Original languageEnglish
Article number15160
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - 9 Nov 2017

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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., & Vlahou, A. (2017). Urinary peptidomics analysis reveals proteases involved in diabetic nephropathy. Scientific Reports, 7(1), [15160]. https://doi.org/10.1038/s41598-017-15359-9