||Wang Y, Heilig K, Saunders T, Minto A, Deb DK, Chang A, Brosius F, Monteiro C,
||Frank Brosius on 8/11/2010
||American journal of physiology. Renal physiology
|Volume : Pages
||299 : F99 - F111
||Previous work identified an important role for hyperglycemia in diabetic
nephropathy (The Diabetes Control and Complications Trial Research Group. N Engl
J Med 329: 977-986, 1993; UK Prospective Diabetes Study Group. Lancet 352:
837-853, 1998), and increased glomerular GLUT1 has been implicated. However, the
roles of GLUT1 and intracellular glucose have not been determined. Here, we
developed transgenic GLUT1-overexpressing mice (GT1S) to characterize the roles
of GLUT1 and intracellular glucose in the development of glomerular disease
without diabetes. GLUT1 was overexpressed in glomerular mesangial cells (MC) of
C57BL6 mice, a line relatively resistant to diabetic nephropathy. Blood
pressure, blood glucose, glomerular morphometry, matrix proteins, cell
signaling, transcription factors, and selected growth factors were examined.
Kidneys of GT1S mice overexpressed GLUT1 in glomerular MCs and small vessels,
rather than renal tubules. GT1S mice were neither diabetic nor hypertensive.
Glomerular GLUT1, glucose uptake, mean capillary diameter, and mean glomerular
volume were all increased in the GT1S mice. Moderately severe glomerulosclerosis
(GS) was established by 26 wk of age in GT1S mice, with increased glomerular
type IV collagen and fibronectin. Modest increases in glomerular basement
membrane thickness and albuminuria were detected with podocyte foot processes
largely preserved, in the absence of podocyte GLUT1 overexpression. Activation
of glomerular PKC, along with increased transforming growth factor-beta1,
VEGFR1, VEGFR2, and VEGF were all detected in glomeruli of GT1S mice, likely
contributing to GS. The transcription factor NF-kappaB was also activated.
Overexpression of glomerular GLUT1, mimicking the diabetic GLUT1 response,
produced numerous features typical of diabetic glomerular disease, without
diabetes or hypertension. This suggested GLUT1 may play an important role in the
development of diabetic GS.