Podocyte-specific overexpression of GLUT1 surprisingly reduces mesangial matrix expansion in diabetic nephropathy in mice.
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.
Zhang
Hongyu
H
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-0680, USA.
Schin
MaryLee
M
Saha
Jharna
J
Burke
Kathleen
K
Holzman
Lawrence B
LB
Filipiak
Wanda
W
Saunders
Thomas
T
Xiang
Minghui
M
Heilig
Charles W
CW
Brosius
Frank C
FC
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000375:Aging; D000419:Albuminuria / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D005215:Fasting / Q000097:blood; D005353:Fibronectins / Q000378:metabolism; D005920:Glomerular Mesangium / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050199:Podocytes / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; C114545:CD2-associated protein; D003598:Cytoskeletal Proteins; D005353:Fibronectins; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D047908:Intracellular Signaling Peptides and Proteins; C486606:Kirrel1 protein, mouse; D008565:Membrane Proteins; C407223:NPHS2 protein; C495679:Slc2a1 protein, rat; C495693:Slc2a4 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse