Podocyte-specific overexpression of GLUT1 surprisingly reduces mesangial matrix
expansion in diabetic nephropathy in mice.
Authors Zhang H, Schin M, Saha J, Burke K, Holzman LB, Filipiak W, Saunders T, Xiang M,
Heilig CW, Brosius FC
Submitted By Frank Brosius on 8/11/2010
Status Published
Journal American journal of physiology. Renal physiology
Year 2010
Date Published 7/1/2010
Volume : Pages 299 : F91 - F98
PubMed Reference 20375116
Abstract Increased expression of the facilitative glucose transporter, GLUT1, leads to
glomerulopathy that resembles diabetic nephropathy, whereas prevention of
enhanced GLUT1 expression retards nephropathy. While many of the GLUT1-mediated
effects are likely due to mesangial cell effects, we hypothesized that increased
GLUT1 expression in podocytes also contributes to the progression of diabetic
nephropathy. Therefore, we generated two podocyte-specific GLUT1 transgenic
mouse lines (driven by a podocin promoter) on a db/m C57BLKS background. Progeny
of the two founders were used to generate diabetic db/db and control db/m
littermate mice. Immunoblots of glomerular lysates showed that transgenic mice
had a 3.5-fold (line 1) and 2.1-fold (line 2) increase in GLUT1 content compared
with wild-type mice. Both lines showed similar increases in fasting blood
glucose and body weights at 24 wk of age compared with wild-type mice. Mesangial
index (percent PAS-positive material in the mesangial tuft) increased 88% (line
1) and 75% (line 2) in the wild-type diabetic mice but only 48% (line 1) and 39%
(line 2) in the diabetic transgenic mice (P < 0.05, transgenic vs. wild-type
mice). This reduction in mesangial expansion was accompanied by a reduction in
fibronectin accumulation, and vascular endothelial growth factor (VEGF) levels
increased only half as much in the transgenic diabetic mice as in wild-type
diabetic mice. Levels of nephrin, neph1, CD2AP, podocin, and GLUT4 were not
significantly different in transgenic compared with wild-type mice. Taken
together, increased podocyte GLUT1 expression in diabetic mice does not
contribute to early diabetic nephropathy; surprisingly, it protects against
mesangial expansion and fibronectin accumulation possibly by blunting podocyte
VEGF increases.

Investigators with authorship
Frank BrosiusUniversity of Arizona