on May 27, 2003
Published online before print May 27, 2003, doi: 10.1161/01.HYP.0000075949.19968.EF
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Submitted on December 9, 2003
From the Department of Diabetes, Endocrinology, and Internal Medicine, GKT School of Medicine, Guy's Hospital (L.G., G.C.V., V.R., D.B., S.T., G.G.), King's College London, UK; the Nephrology and Hypertension Division, Department of Veterans Affairs Medical Center and University of Miami School of Medicine (L.R.), Miami, Fla; the Division of Nephrology and Hypertension, Henry Ford Hospital (P.C.), Detroit, Mich; the Department of Histopathology, St James Hospital, Leeds University (B.H.), Leeds, UK; and the Department of Metabolism and Diabetes, Istituto Auxologico Italiano (S.M.), Milano, Italy. * To whom correspondence should be addressed. E-mail: luigi.gnudi{at}kcl.ac.uk.
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
Revised on December 26, 2002
GLUT-1 Overexpression. Link Between Hemodynamic and Metabolic Factors in Glomerular Injury?
Luigi Gnudi*;
1 (TGF-1), 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-1 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
0.03). This was accompanied by a 2.7-fold upregulation of TGF-1 protein expression in glomeruli of DSH compared with DSN rats (P=0.02). TGF-1 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 P0.01), which could be blocked with an anti TGF-1-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.
Key words: hypertension, experimental • mesangium • stress • transforming growth factors
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