Dataset Information

Urinary PRM analysis of early type 1 diabetes

ABSTRACT: Chronic hyperglycemia is known to disrupt the proteolytic milieu, initiating compensatory and maladaptive pathways in the diabetic kidney. Such changes in intrarenal proteolysis can be captured in the urinary peptidome. We thus examined the urinary peptidomes of otherwise healthy youths with type 1 diabetes and their non-diabetic peers. This cross-sectional study included two separate cohorts for the discovery (N = 30) and initial validation (N = 30) of differential peptide excretion. Peptide bioactivity was predicted using PeptideRanker and subsequently verified in vitro. Proteasix and the Nephroseq database were used to identify putative proteases responsible for peptide generation and examine their expression in diabetic nephropathy. A total of 6550 urinary peptides were identified in the discovery analysis. Of the 15 differentially excreted peptides (P < 0.05), seven derived from a small region (589SGSVIDQSRVLNLGPITRK607) near the C-terminus of uromodulin. Excretion rates of five uromodulin peptides were validated using parallel reaction monitoring (P < 0.05). One of the validated peptides activated TLR4-dependent NFκB signalling, stimulated cytokine release, and enhanced neutrophil migration in vitro. In silico analyses identified several possible proteases such hepsin, cathepsin B, and meprin A to be responsible for generating these peptides. In summary, uromodulin processing in the kidney produces bioactive peptides, which may be differentially excreted in early diabetes.

ORGANISM(S): Homo Sapiens

SUBMITTER: Julie Van

PROVIDER: PXD012389 | panorama | Wed Jan 01 00:00:00 GMT 2020

REPOSITORIES: PanoramaPublic

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Publications

Peptidomic Analysis of Urine from Youths with Early Type 1 Diabetes Reveals Novel Bioactivity of Uromodulin Peptides <i>In Vitro</i>.

Van Julie A D JAD Clotet-Freixas Sergi S Zhou Joyce J Batruch Ihor I Sun Chunxiang C Glogauer Michael M Rampoldi Luca L Elia Yesmino Y Mahmud Farid H FH Sochett Etienne E Diamandis Eleftherios P EP Scholey James W JW Konvalinka Ana A

Molecular & cellular proteomics : MCP 20191226 3

Chronic hyperglycemia is known to disrupt the proteolytic milieu, initiating compensatory and maladaptive pathways in the diabetic kidney. Such changes in intrarenal proteolysis are captured by the urinary peptidome. To elucidate the early kidney response to chronic hyperglycemia, we conducted a peptidomic investigation into urines from otherwise healthy youths with type 1 diabetes and their non-diabetic peers using unbiased and targeted mass spectrometry-based techniques. This cross-sectional s ...[more]

PMID: 31879271

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Project description:Dengue and Zika are two mosquito-borne diseases of great concern, affecting mainly the tropical and subtropical regions worldwide. The arrival of Zika virus (ZIKV) in dengue virus (DENV) endemic areas imposed challenges for differential diagnosis and the development of candidate vaccines. The use of peptides has shown great potential to achieve these goals. We aimed to identify the linear epitope profile recognized by the serum samples of dengue and Zika patients in the E and NS1 proteins of DENV and ZIKV to select peptides with the potential for the development of diagnostic tests and vaccines. Analysis of a peptide microarray platform with serum samples of dengue and Zika patients demonstrated that the epitopes were evenly distributed across the entire viral proteins, showing no preference for particular regions. However, several epitopes were within epitope hot spots constituted by clusters of peptides recognized in more than 30% of the sub-arrays analyzed with individual or pools of serum samples. The serum samples of dengue and Zika patients showed a high level of cross-reaction for epitopes in the DENV and ZIKV proteins. Analysis of an additional peptide microarray platform containing selected peptides based on the results of the first screening showed that three peptides (DENV: TQGEPSLNEEQDKRF and TQTVGPWHLGKLEID; ZIKV: LELDPPFGDSYIVIG), highly specific for their cognate viruses (p<0.05), were within the epitope hot spots; however, these peptides showed low detection rates (32.5, 35.0, and 28.6%, respectively). We also found two peptides (DENV: WEVEDYGFGVFTTNI and LELDFDLCEGTTVVV) in the epitope hot spots detected by both dengue and Zika patients with similarly high rates (arbitrary detection rate cut-off threshold of ≥40%). The epitope hot spots harbor several immunodominant epitopes recognized by a higher number of individuals when compared to the 15 aa sequence peptides. Therefore, the entire epitope hot spots, spanning up to ~30 aa, would have more potential than peptides of only 15 aa to serve as antigens in diagnostic tests and vaccine developments.

Dataset Information

Urinary PRM analysis of early type 1 diabetes

Publications

Peptidomic Analysis of Urine from Youths with Early Type 1 Diabetes Reveals Novel Bioactivity of Uromodulin Peptides <i>In Vitro</i>.

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