Urine peptidome analysis in cardiorenal syndrome reflects molecular processes

Abstract

The cardiorenal syndrome (CRS) is defined as the confluence of heart-kidney dysfunction. This study investigates the molecular differences at the level of the urinary peptidome between CRS patients and controls and their association to disease pathophysiology. The urinary peptidome of CRS patients (n = 353) was matched for age and sex with controls (n = 356) at a 1:1 ratio. Changes in the CRS peptidome versus controls were identified after applying the Mann–Whitney test, followed by correction for multiple testing. Proteasix tool was applied to investigate predicted proteases involved in CRS-associated peptide generation. Overall, 559 differentially excreted urinary peptides were associated with CRS patients. Of these, 193 peptides were specifically found in CRS when comparing with heart failure and chronic kidney disease urinary peptide profiles. Proteasix predicted 18 proteases involved in > 1% of proteolytic cleavage events including multiple forms of MMPs, proprotein convertases, cathepsins and kallikrein 4. Forty-four percent of the cleavage events were produced by 3 proteases including MMP13, MMP9 and MMP2. Pathway enrichment analysis supported that ECM-related pathways, fibrosis and inflammation were represented. Collectively, our study describes the changes in urinary peptides of CRS patients and potential proteases involved in their generation, laying the basis for further validation.

Salivary peptidome analysis and protease prediction during orthodontic treatment with fixed appliances

“…The additional 16 novel proteases could be attributed to changes in the Proteasix algorithm since the original publication 4 , age-related differences in the WMS proteome and peptidome 20 or more likely the effect of OTM. From the 73, 24 had > 1% cleavage 16 with calpains, MMPs, cathepsins the most prevalent groups.…”

“…For each protease, the percentage of cleavage from total cleavage events for each participant was calculated and a percentage threshold of cleavage set at 1% to consider activity of a particular protease (Fig. 2) 16 . Twenty-four proteases had a percentage threshold of cleavage > 1% and amongst these, calpains, MMPs and cathepsins were the most prevalent groups and potentially implicated in the generation of WMS peptides at all time-points.…”

Clinical applications of plasma proteomics and peptidomics: Towards precision medicine

“…To address this, scientists have developed the Proteasix software, an open-source peptide-centric tool that can be used to predict proteases for the naturally occurring peptides production in silico [154,158]. Integrating information from a number of protease databases such as Merops, CutDB, Brenda and UniProtKB, Proteasix can accurately elucidate cleavage sites from peptide sequence inputs, and reveal proteases that may be involved in endogenous peptide generation [153,159,160]. This valuable tool can facilitate linking of peptide fragments to predicted protease activity and thus uncover possible disease mechanisms, which will still need to be confirmed experimentally [154,157,160].…”

Urinary Proteomic Signature in Acute Decompensated Heart Failure: Advances into Molecular Pathophysiology

“…Sixteen proteins were identified by MS/MS working on the lift mode after peptide fragmentation of the three monoisotopic peaks with higher intensity (Table 1 with additional information in Supplementary Table S3). Selected peptides had a median length of 11 (9)(10)(11)(12)(13)(14) amino acids. Seven peptides presented a cysteine (C) carbamidomethylation and one peptide had a methionine (M) oxidation; both types of modifications were taken into account for the fragment mass analysis and MASCOT MS/MS ion search.…”

“…MS analysis has emerged as a powerful tool in proteomics to identify and characterize proteins and protein complexes in biological samples including blood, urine, tissues, and cells. MS can be used for high-throughput identification of proteins in complex mixtures or after protein separation by different methods including two-dimensional gel electrophoresis (2DE) [11,12]. In previous studies, we used a top-down strategy (analysis of intact protein) based on 2DE coupled to matrix-assisted laser desorption and ionization time of flight (MALDI-TOF/TOF) mass spectrometry to describe changes of the plasma proteome in early stages of acute myocardial infarction [13,14] or in isolated platelets of subjects with metabolic disorders [15].…”