title: GLUT-1 overexpression: Link between hemodynamic and metabolic factors in glomerular injury?
abstract: Mesangial matrix deposition is the hallmark of hypertensive and diabetic glomerulopathy. At similar levels of systemic hypertension, Dahl salt-sensitive but not spontaneously hypertensive rats (SHR) develop glomerular hypertension, which is accompanied by upregulation of transforming growth factor beta1 (TGF-beta1), mesangial matrix expansion, and sclerosis. GLUT-1 is ubiquitously expressed and is the predominant glucose transporter in mesangial cells. In mesangial cells in vitro, GLUT-1 overexpression increases basal glucose transport, resulting in excess fibronectin and collagen production. TGF-beta1 has been shown to upregulate GLUT-1 expression. We demonstrated that in hypertensive Dahl salt-sensitive (S) rats fed 4% NaCl (systolic blood pressure [SBP]: 236+/-9 mm Hg), but not in similarly hypertensive SHR (SBP: 230+/-10 mm Hg) or their normotensive counterparts (Dahl S fed 0.5% NaCl, SBP: 145+/-5 mm Hg; and Wistar-Kyoto, SBP: 137+/-3 mm Hg), there was an 80% upregulation of glomerular GLUT-1 protein expression (P< or =0.03). This was accompanied by a 2.7-fold upregulation of TGF-beta1 protein expression in glomeruli of DSH compared with DSN rats (P=0.02). TGF-beta1 expression was not upregulated and did not differ in the glomeruli of Wistar-Kyoto and SHR rats. As an in vitro surrogate of the in vivo hemodynamic stress imposed by glomerular hypertension, we used mechanical stretching of human and rat mesangial cells. We found that after 33 hours of stretching, mesangial cells overexpressed GLUT-1 (40%) and showed an increase in basal glucose transport of similar magnitude (both P< or =0.01), which could be blocked with an anti TGF-beta1-neutralizing antibody. These studies suggest a novel link between hemodynamic and metabolic factors that may cooperate in inducing progressive glomerular injury in conditions characterized by glomerular hypertension.
authors.affiliation: Department of Diabetes, Endocrinology, and Internal Medicine, King's College, 5th Floor, Thomas Guy House, Guy's Hospital, London SE1 9RT, UK. luigi.gnudi@kcl.ac.uk
authors.forename: Luigi
authors.initials: L
authors.lastname: Gnudi
authors.forename: GianCarlo
authors.initials: G
authors.lastname: Viberti
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Raij
authors.forename: Veronica
authors.initials: V
authors.lastname: Rodriguez
authors.forename: Davina
authors.initials: D
authors.lastname: Burt
authors.forename: Pedro
authors.initials: P
authors.lastname: Cortes
authors.forename: Barry
authors.initials: B
authors.lastname: Hartley
authors.forename: Stephen
authors.initials: S
authors.lastname: Thomas
authors.forename: Sabrina
authors.initials: S
authors.lastname: Maestrini
authors.forename: Gabriella
authors.initials: G
authors.lastname: Gruden
mesh_terms: D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D005920:Glomerular Mesangium / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1; D006439:Hemodynamics; D006801:Humans; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology; D006977:Hypertension, Renal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015151:Immunoblotting; D007150:Immunohistochemistry; D007672:Kidney Cortex / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis* / Q000276:immunology; D051381:Rats; D020303:Rats, Inbred Dahl; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013314:Stress, Mechanical; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000502:physiology; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation
chemical_list: D051272:Glucose Transporter Type 1; D009004:Monosaccharide Transport Proteins; C495677:SLC2A1 protein, human; C495679:Slc2a1 protein, rat; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D005947:Glucose