Journal Article

Urinary proteomics links keratan sulfate degradation and lysosomal enzymes to early type 1 diabetes

Sergi Clotet-Freixas, Ana Konvalinka, Anne-Christin Hauschild, Eleftherios P. Diamandis, James W. Scholey, Etienne Sochett, Julie A.D. Van, Igor Jurisica, Ihor Batruch, Farid H. Mahmud, Yesmino Elia

2020

Overview

Diabetes is the leading cause of end-stage renal disease worldwide. Our understanding of the early kidney response to chronic hyperglycemia remains incomplete. To address this, we first investigated the urinary proteomes of otherwise healthy youths with and without type 1 diabetes and subsequently examined the enriched pathways that might be dysregulated in early disease using systems biology approaches. This cross-sectional study included two separate cohorts for the discovery (N = 30) and internal validation (N = 30) of differentially excreted proteins. Discovery proteomics was performed on a Q Exactive Plus hybrid quadrupole-orbitrap mass spectrometer. We then searched the pathDIP, KEGG, and Reactome databases to identify enriched pathways in early diabetes; the Integrated Interactions Database to retrieve protein-protein interaction data; and the PubMed database to compare fold changes of our signature proteins with those published in similarly designed studies. Proteins were selected for internal validation based on pathway enrichment and availability of commercial enzyme-linked immunosorbent assay kits. Of the 2451 proteins identified, 576 were quantified in all samples from the discovery cohort; 34 comprised the urinary signature for early diabetes after Benjamini-Hochberg adjustment (Q < 0.05). The top pathways associated with this signature included lysosome, glycosaminoglycan degradation, and innate immune system (Q < 0.01). Notably, all enzymes involved in keratan sulfate degradation were significantly elevated in urines from youths with diabetes (|fold change| > 1.6). Increased urinary excretion of monocyte differentiation antigen CD14, hexosaminidase A, and lumican was also observed in the validation cohort (P < 0.05). Twenty-one proteins from our signature have been reported elsewhere as potential mediators of early diabetes. In this study, we identified a urinary proteomic signature for early type 1 diabetes, of which lysosomal enzymes were major constituents. Our findings highlight novel pathways such as keratan sulfate degradation in the early kidney response to hyperglycemia.

• Publisher: Public Library of Science (PLoS),Public Library of Science
• Subject: Adolescent / Adult / Age / Analysis / Antigens / Biology and Life Sciences / Biomedical laboratory equipment / Biopsy / CD14 antigen / Child / Chronic kidney failure / Complications and side effects / Computer science / Degradation / Development and progression / Diabetes / Diabetes mellitus / Diabetes mellitus (insulin dependent) / Diabetes Mellitus, Type 1 / Diseases / End-stage renal disease / Enrichment / Enzyme-linked immunosorbent assay / Enzymes / Extracellular Matrix Proteins / Female / Glycosaminoglycans / Health aspects / Health care networks / Hospitals / Humans / Hyperglycemia / Immune system / Innate immunity / Keratan Sulfate / Kidney / Kidney diseases / Kidneys / Laboratories / Lysosomal enzymes / Lysosomes / Male / Mass Spectrometry / Medicine / Medicine and Health Sciences / Methods / Monocytes / Mucopolysaccharides / Nephrology / Novels / Peptides / Physical Sciences / Protein folding / Protein interaction / Protein-protein interactions / Proteins / Proteinuria / Proteome / Proteomics / Q / Quadrupoles / Questions and answers / R / Research Article / Risk factors / Science / Sulfates / Type 1 diabetes / Urinalysis / Urine / Young Adult / Youth