title: Proteases and protease inhibitors of urinary extracellular vesicles in diabetic nephropathy.
abstract: Diabetic nephropathy (DN) is one of the major complications of diabetes mellitus (DM), leads to chronic kidney disease (CKD), and, ultimately, is the main cause for end-stage kidney disease (ESKD). Beyond urinary albumin, no reliable biomarkers are available for accurate early diagnostics. Urinary extracellular vesicles (UEVs) have recently emerged as an interesting source of diagnostic and prognostic disease biomarkers. Here we used a protease and respective protease inhibitor array to profile urines of type 1 diabetes patients at different stages of kidney involvement. Urine samples were divided into groups based on the level of albuminuria and UEVs isolated by hydrostatic dialysis and screened for relative changes of 34 different proteases and 32 protease inhibitors, respectively. Interestingly, myeloblastin and its natural inhibitor elafin showed an increase in the normo- and microalbuminuric groups. Similarly, a characteristic pattern was observed in the array of protease inhibitors, with a marked increase of cystatin B, natural inhibitor of cathepsins L, H, and B as well as of neutrophil gelatinase-associated Lipocalin (NGAL) in the normoalbuminuric group. This study shows for the first time the distinctive alterations in comprehensive protease profiles of UEVs in diabetic nephropathy and uncovers intriguing mechanistic, prognostic, and diagnostic features of kidney damage in diabetes.
authors: Centre for Bioanalytical Sciences (CBAS), Dublin City University, Dublin 9, Ireland.
authors: Luca
authors: 0000-0002-6225-8598
authors: L
authors: Musante
authors: Centre for Bioanalytical Sciences (CBAS), Dublin City University, Dublin 9, Ireland.
authors: Dorota
authors: D
authors: Tataruch
authors: Centre for Bioanalytical Sciences (CBAS), Dublin City University, Dublin 9, Ireland.
authors: Dongfeng
authors: D
authors: Gu
authors: Centre for Bioanalytical Sciences (CBAS), Dublin City University, Dublin 9, Ireland.
authors: Xinyu
authors: X
authors: Liu
authors: Folkhälsan Institute of Genetics, Folkhälsan Research Center, 00100 Helsinki, Finland ; Department of Medicine, Division of Nephrology, Helsinki University Central Hospital, 00100 Helsinki, Finland ; Diabetes and Obesity, Research Program Unit, University of Helsinki, 00100 Helsinki, Finland.
authors: Carol
authors: C
authors: Forsblom
authors: Folkhälsan Institute of Genetics, Folkhälsan Research Center, 00100 Helsinki, Finland ; Department of Medicine, Division of Nephrology, Helsinki University Central Hospital, 00100 Helsinki, Finland ; Diabetes and Obesity, Research Program Unit, University of Helsinki, 00100 Helsinki, Finland ; Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
authors: Per-Henrik
authors: PH
authors: Groop
authors: Centre for Bioanalytical Sciences (CBAS), Dublin City University, Dublin 9, Ireland.
authors: Harry
authors: H
authors: Holthofer
mesh_terms: D000328:Adult; D000419:Albuminuria / Q000150:complications / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D055313:Cystatin B / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000652:urine; D003928:Diabetic Nephropathies / Q000378:metabolism*; D000067128:Extracellular Vesicles / Q000737:chemistry*; D005260:Female; D005374:Filtration; D005919:Glomerular Filtration Rate; D064368:Healthy Volunteers; D006801:Humans; D007676:Kidney Failure, Chronic / Q000378:metabolism; D008297:Male; D053146:Myeloblastin / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*; D011480:Protease Inhibitors / Q000737:chemistry*; D012307:Risk Factors; D055815:Young Adult
chemical_list: D015415:Biomarkers; D011480:Protease Inhibitors; D055313:Cystatin B; D010447:Peptide Hydrolases; D053146:Myeloblastin