GLUT-1 overexpression: Link between hemodynamic and metabolic factors in glomerular injury?
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.
Gnudi
Luigi
L
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
Viberti
GianCarlo
G
Raij
Leopoldo
L
Rodriguez
Veronica
V
Burt
Davina
D
Cortes
Pedro
P
Hartley
Barry
B
Thomas
Stephen
S
Maestrini
Sabrina
S
Gruden
Gabriella
G
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
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