Updated project metadata. Urinary proteome was analyzed and quantified by Tandem Mass Tag (TMT) labeling followed by bioinformatics analysis to study DN pathophysiology and to identify biomarkers of clinical outcome. We included type 2 diabetic normotensive non-obese males with and without incipient DN (microalbuminuria). Sample collection included blood and urine at baseline (control and DN-basal) and, in DN patients, after 3 months of losartan treatment (DN-treated). Urinary proteome analysis identified 166 differentially abundant proteins between controls and DN patients, 27 comparing DN-treated and DN-basal patients, and 182 between DN-treated patients and controls. Mathematical modeling analysis identified 80 key proteins involved in DN pathophysiology, 15 in losartan effect and 7 of these 95 are essential in both processes. VCAM-1 and neprilysin are the only ones that are differentially expressed in the urinary proteome. We observed an increase of VCAM-1 urine levels in DN-basal patients compared to diabetic controls and an increase of urinary neprilysin in DN-treated patients with persistent albuminuria, the latter confirmed by ELISA . Our results point to neprilysin and VCAM-1 as potential candidates in DN pathology and treatment.