title: Caveolin-1 deficiency protects against mesangial matrix expansion in a mouse model of type 1 diabetic nephropathy.
abstract: OBJECTIVE
  Glomerular matrix protein accumulation, mediated largely by resident mesangial cells (MCs), is central to the pathogenesis of diabetic nephropathy. We previously showed that caveolin (CAV)-1/caveolae mediate matrix upregulation by MCs in response to high glucose and TGFβ, two important pathogenic mediators of diabetic glomerular sclerosis. Here, we evaluated the in vivo role of CAV-1/caveolae in the development of diabetic nephropathy.
  
  
  METHODS
  Diabetes was induced in Cav1-knockout (KO) mice and their wild-type (WT) counterparts by streptozotocin injection. After 10 months, kidneys were evaluated for the development of nephropathy, including glomerular sclerosis and upregulation of matrix proteins. Parallel experiments assessing glucose-induced matrix upregulation were carried out in MCs isolated from KO mice.
  
  
  RESULTS
  KO diabetic mice developed hyperglycaemia and renal hypertrophy, but were protected from developing albuminuria and glomerular sclerosis compared with WT mice. KO mice were significantly protected from the upregulation of glomerular collagen I, fibronectin, connective tissue growth factor (CTGF) and TGFβ. In vitro, glucose induced collagen I A1 promoter activation and collagen I, fibronectin and CTGF protein upregulation in WT but not KO MCs. Re-expression of Cav1 in KO cells restored this response.
  
  
  CONCLUSIONS
  Cav1 deletion rendered significant protection from glomerular matrix accumulation and albuminuria in a mouse model of type 1 diabetes. These studies provide a foundation for the development of renal-targeted interference with CAV-1/caveolae as a novel approach to the treatment of diabetic nephropathy.
authors.affiliation: Division of Nephrology, McMaster University, St Joseph's Hospital, 50 Charlton Ave East, Rm T3311, Hamilton, ON, Canada L8N 4A6.
authors.forename: T H
authors.initials: TH
authors.lastname: Guan
authors.forename: G
authors.initials: G
authors.lastname: Chen
authors.forename: B
authors.initials: B
authors.lastname: Gao
authors.forename: M R
authors.initials: MR
authors.lastname: Janssen
authors.forename: L
authors.initials: L
authors.lastname: Uttarwar
authors.forename: A J
authors.initials: AJ
authors.lastname: Ingram
authors.forename: J C
authors.initials: JC
authors.lastname: Krepinsky
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000172:deficiency* / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout
chemical_list: D051242:Caveolin 1