title: Deletion of UNC5B in Kidney Epithelium Exacerbates Diabetic Nephropathy in Mice.
abstract: BACKGROUND
  Guidance cue netrin-1 was shown to have protective effects in diabetic nephropathy. However, the role of its receptor UNC5B in diabetic kidney disease is unknown. Moreover, whether netrin-1 is protective against diabetic kidney disease in a genetic model of nephropathy and in the nephropathy prone DBA background is also unknown. The aim of this study was to determine the significance of UNC5B in tubular epithelial cells in chronic kidney disease due to diabetes and evaluate whether netrin-1 is also protective in the case of a nephropathy-prone mouse.
  
  
  METHODS
  Proximal tubular epithelium-specific UNC5B knockout mice as well as heterozygous UNC5B knockout mice were used to determine the roles of UNC5B in nephropathy. Diabetes was induced in these tissue-specific knockout, heterozygous and WT mice, and albuminuria was then monitored.
  
  
  RESULTS
  WT and heterozygous diabetic mice developed significant albuminuria at 8 weeks after induction of diabetes as compared to buffer-treated control mice. However, albuminuria was significantly more pronounced in mice with proximal tubule specific deletion of UNC5B. Transgenic overexpression of netrin-1 in proximal tubules in the DBA background and administration of recombinant netrin-1 to Ins2Akita mice also significantly reduced diabetes-induced albuminuria and suppressed glomerular and interstitial lesions.
  
  
  CONCLUSIONS
  Our data suggested that netrin-1 signaling in proximal tubular epithelium may play a critical role in the protection of kidney against diabetic kidney disease.
authors.affiliation: Department of Medicine and Vascular Biology Center, Georgia Regents University, Augusta, Ga., USA.
authors.forename: Punithavathi
authors.initials: P
authors.lastname: Ranganathan
authors.forename: Riyaz
authors.initials: R
authors.lastname: Mohamed
authors.forename: Calpurnia
authors.initials: C
authors.lastname: Jayakumar
authors.forename: Michael W
authors.initials: MW
authors.lastname: Brands
authors.forename: Ganesan
authors.initials: G
authors.lastname: Ramesh
mesh_terms: D000419:Albuminuria / Q000097:blood; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D006579:Heterozygote; D007687:Kidney Tubules, Proximal; D051379:Mice; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000075386:Netrin Receptors; D000075388:Netrin-1; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1