Urine peptidome in combination with transcriptomics analysis highlights MMP7, MMP14 and PCSK5 for further investigation in chronic kidney disease

PLoS ONE, vol. 17, pp. e0262667

Abstract

Chronic kidney disease (CKD) is characterized by the loss of kidney function. The molecular mechanisms underlying the development and progression of CKD are still not fully understood. Among others, the urinary peptidome has been extensively studied, with several urinary peptides effectively detecting disease progression. However, their link to proteolytic events has not been made yet. This study aimed to predict the proteases involved in the generation of CKD-associated urinary excreted peptides in a well-matched (for age, sex, lack of heart disease) case-control study. The urinary peptide profiles from CKD (n = 241) and controls (n = 240) were compared and statistically analyzed. The in-silico analysis of the involved proteases was performed using Proteasix and proteases activity was predicted based on the abundance changes of the associated peptides. Predictions were cross-correlated to transcriptomics datasets by using the Nephroseq database. Information on the respective protease inhibitors was also retrieved from the MEROPS database. Totally, 303 urinary peptides were significantly associated with CKD. Among the most frequently observed were fragments of collagen types I, II and III, uromodulin, albumin and beta-2-microglobulin. Proteasix predicted 16 proteases involved in their generation. Through investigating CKD-associated transcriptomics datasets, several proteases are highlighted including members of matrix metalloproteinases (MMP7, MMP14) and serine proteases (PCSK5); laying the foundation for further studies towards elucidating their role in CKD pathophysiology.

Authors 4

1. Eleni Petra Aachen Institute for Molecular Cardiovascular Research

   Biomedical Research Foundation of the Academy of Athens · Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, Athens, Greece

   Institute for Molecular Cardiovascular Research, RWTH Aachen University Hospital, Aachen, Germany

2. Justyna Siwy

   Mosaiques Diagnostics and Therapeutics (Germany)

   Affiliation as printed

   Mosaiques Diagnostics GmbH, Hannover, Germany

3. Antonia Vlahou

   Biomedical Research Foundation of the Academy of Athens

   Affiliation as printed

   Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, Athens, Greece

4. Joachim Jankowski corresponding Aachen Institute for Molecular Cardiovascular Research

   Maastricht University · Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Experimental Vascular Pathology, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, Maastricht, The Netherlands

   Institute for Molecular Cardiovascular Research, RWTH Aachen University Hospital, Aachen, Germany