title: Urinary peptidomics provides a noninvasive humanized readout of diabetic nephropathy in mice.
abstract: Nephropathy is among the most frequent complications of diabetes and the leading cause of end-stage renal disease. Despite the success of novel drugs in animal models, the majority of the subsequent clinical trials employing those drugs targeting diabetic nephropathy failed. This lack of translational value may in part be due to an inadequate comparability of human disease and animal models that often capture only a few aspects of disease. Here we overcome this limitation by developing a multimolecular noninvasive humanized readout of diabetic nephropathy based on urinary peptidomics. The disease-modified urinary peptides of 2 type 2 diabetic nephropathy mouse models were identified and compared with previously validated urinary peptide markers of diabetic nephropathy in humans to generate a classifier composed of 21 ortholog peptides. This classifier predicted the response to disease and treatment with inhibitors of the renin-angiotensin system in mice. The humanized classifier was significantly correlated with glomerular lesions. Using a human type 2 diabetic validation cohort of 207 patients, the classifier also distinguished between patients with and without diabetic nephropathy, and their response to renin-angiotensin system inhibition. Thus, a combination of multiple molecular features common to both human and murine disease could provide a significant change in translational drug discovery research in type 2 diabetic nephropathy.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1048, Institute of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Klein
authors.affiliation: Mosaiques Diagnostics and Therapeutics, Hannover, Germany.
authors.forename: Adela
authors.initials: A
authors.lastname: Ramirez-Torres
authors.affiliation: Cardiovascular and Metabolic Disease Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Anette
authors.initials: A
authors.lastname: Ericsson
authors.affiliation: Department of Medicine, Division of Nephrology, University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1048, Institute of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Breuil
authors.affiliation: Mosaiques Diagnostics and Therapeutics, Hannover, Germany.
authors.forename: Justyna
authors.initials: J
authors.lastname: Siwy
authors.affiliation: Mosaiques Diagnostics and Therapeutics, Hannover, Germany; British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, Faculty of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Harald
authors.initials: H
authors.lastname: Mischak
authors.affiliation: Cardiovascular and Metabolic Disease Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Xiao-Rong
authors.initials: XR
authors.lastname: Peng
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1048, Institute of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France; Inserm, UMR 1188 Diabète athérothrombose Thérapies Réunion Océan Indien (DéTROI), plateforme CYROI, Sainte-Clotilde, France. Electronic address: jean-loup.bascands@inserm.fr.
authors.forename: Jean-Loup
authors.initials: JL
authors.lastname: Bascands
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1048, Institute of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France. Electronic address: joost-peter.schanstra@inserm.fr.
authors.forename: Joost P
authors.initials: JP
authors.lastname: Schanstra
mesh_terms: D015415:Biomarkers / Q000652:urine*; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D003928:Diabetic Nephropathies / Q000209:etiology / Q000652:urine*; D005260:Female; D006801:Humans; D008297:Male; D010455:Peptides / Q000652:urine*; D020543:Proteome
chemical_list: D015415:Biomarkers; D010455:Peptides; D020543:Proteome
keywords: albuminuria; angiotensin-converting enzyme inhibitor; diabetic nephropathy; proteomic analysis; urine