title: Urinary semaphorin 3A correlates with diabetic proteinuria and mediates diabetic nephropathy and associated inflammation in mice.
abstract: Semaphorin 3A (sema3A) was recently identified as an early diagnostic biomarker of acute kidney injury. However, its role as a biomarker and/or mediator of chronic kidney disease (CKD) related to diabetic nephropathy is unknown. We examined the expression of sema3A in diabetic animal models and in humans and tested whether sema3A plays a pathogenic role in the development of diabetic nephropathy. The expression of sema3A was localized to podocytes and epithelial cells in distal tubules and collecting ducts in control animals, and its expression was increased following the induction of diabetes. Quantification of sema3A urinary excretion in three different diabetic mouse models showed that excretion was increased as early as 2 weeks after the induction of diabetes and increased over time, in conjunction with the development of nephropathy. Consistent with the mouse data, increased sema3A urinary excretion was detected in diabetic patients with albuminuria, particularly in those with macroalbuminuria. Genetic ablation of sema3A or pharmacological inhibition with a novel sema3A inhibitory peptide was protected against diabetes-induced albuminuria, kidney fibrosis, inflammation, oxidative stress, and renal dysfunction. We conclude that sema3A is both a biomarker and a mediator of diabetic kidney disease and could be a promising therapeutic target in diabetic nephropathy. Key messages Diabetes induced sema3A excretion in urine. Increased semaphorin 3A was associated with severity of albuminuria. Seme3A-mediated diabetes induced glomerulosclerosis. Peptide-based inhibition of semaphorin3A suppressed diabetic nephropathy.
authors.affiliation: Department of Medicine, Vascular Biology Center, Georgia Regents University, CB-3702, 1459 Laney-Walker Blvd, Augusta, GA, 30912, USA.
authors.forename: Riyaz
authors.initials: R
authors.lastname: Mohamed
authors.forename: Punithavathi
authors.initials: P
authors.lastname: Ranganathan
authors.forename: Calpurnia
authors.initials: C
authors.lastname: Jayakumar
authors.forename: Ferdau L
authors.initials: FL
authors.lastname: Nauta
authors.forename: Ron T
authors.initials: RT
authors.lastname: Gansevoort
authors.forename: Neal L
authors.initials: NL
authors.lastname: Weintraub
authors.forename: Michael
authors.initials: M
authors.lastname: Brands
authors.forename: Ganesan
authors.initials: G
authors.lastname: Ramesh
mesh_terms: D000419:Albuminuria / Q000150:complications / Q000652:urine*; D000595:Amino Acid Sequence; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000652:urine*; D003928:Diabetic Nephropathies / Q000150:complications / Q000473:pathology* / Q000517:prevention & control / Q000652:urine*; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000652:urine*; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000627:therapeutic use; D040121:Semaphorin-3A / Q000032:analysis / Q000037:antagonists & inhibitors / Q000652:urine*
chemical_list: D010455:Peptides; D040121:Semaphorin-3A