title: Role of TGF-beta/GLUT1 axis in susceptibility vs resistance to diabetic glomerulopathy in the Milan rat model.
abstract: BACKGROUND
  GLUT1 upregulation and increased glucose transport activity may contribute to extracellullar matrix (ECM) accumulation characterizing diabetic nephropathy (DN). Rats of the Milan hypertensive strain (MHS) are resistant to both hypertensive and diabetic renal disease, due to a haemodynamic protection. On the contrary, those of the Milan normotensive strain (MNS) develop spontaneous glomerulosclerosis, and when rendered diabetic, show typical morphological and haemodynamic changes.
  
  
  METHODS
  To assess whether susceptibility to diabetic glomerulopathy in MNS rats is associated with higher glucose transporter 1 (GLUT1) expression (and glucose transport activity) vs MHS rats, diabetic and nondiabetic MNS and MHS rats were followed for 6 months and mesangial cells derived from these animals were exposed to high glucose (HG) vs normal glucose (NG) conditions.
  
  
  RESULTS
  Glomerular expression of GLUT1 protein and ECM and transforming growth factor-beta (TGF-beta) mRNA was significantly upregulated in diabetic vs nondiabetic MNS, but not MHS rats. Upon exposure to HG and/or TGF-beta, mesangial cells from 1- and 8-month-old MNS rats showed higher glucose transport activity and GLUT1 membrane expression than those from age-matched MHS rats. Likewise, ECM and TGF-beta production increased more markedly in response to HG and/or TGF-beta in MNS vs MHS mesangial cells.
  
  
  CONCLUSIONS
  These data indicate that susceptibility to diabetic glomerulopathy in MNS rats is associated with increased GLUT1-dependent glucose transport activity in response to hyperglycaemia and/or TGF-beta, which may amplify ECM overproduction. Conversely, the haemodynamic protection from glomerulosclerosis in MHS rats is associated with lack of upregulation of TGF-beta/GLUT1 axis, thus supporting the concept that this axis may represent the link between haemodynamic and metabolic mechanisms of injury.
authors.affiliation: Department of Clinical Sciences, La Sapienza University, Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Ricci
authors.forename: Carla
authors.initials: C
authors.lastname: Iacobini
authors.forename: Giovanna
authors.initials: G
authors.lastname: Oddi
authors.forename: Lorena
authors.initials: L
authors.lastname: Amadio
authors.forename: Stefano
authors.initials: S
authors.lastname: Menini
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Rastaldi
authors.forename: Aurora
authors.initials: A
authors.lastname: Frasheri
authors.forename: Flavia
authors.initials: F
authors.lastname: Pricci
authors.forename: Francesco
authors.initials: F
authors.lastname: Pugliese
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pugliese
mesh_terms: D000818:Animals; D048909:Diabetes Complications / Q000209:etiology*; D003921:Diabetes Mellitus, Experimental; D004198:Disease Susceptibility; D005109:Extracellular Matrix / Q000235:genetics; D005921:Glomerulonephritis / Q000209:etiology*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D051272:Glucose Transporter Type 1 / Q000502:physiology*; D006943:Hyperglycemia / Q000150:complications; D006973:Hypertension; D007113:Immunity, Innate; D051381:Rats; D011922:Rats, Mutant Strains; D016212:Transforming Growth Factor beta / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D051272:Glucose Transporter Type 1; C495679:Slc2a1 protein, rat; D016212:Transforming Growth Factor beta; D005947:Glucose