title: Podocyte-specific overexpression of GLUT1 surprisingly reduces mesangial matrix expansion in diabetic nephropathy in mice.
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.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-0680, USA.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.forename: MaryLee
authors.initials: M
authors.lastname: Schin
authors.forename: Jharna
authors.initials: J
authors.lastname: Saha
authors.forename: Kathleen
authors.initials: K
authors.lastname: Burke
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Holzman
authors.forename: Wanda
authors.initials: W
authors.lastname: Filipiak
authors.forename: Thomas
authors.initials: T
authors.lastname: Saunders
authors.forename: Minghui
authors.initials: M
authors.lastname: Xiang
authors.forename: Charles W
authors.initials: CW
authors.lastname: Heilig
authors.forename: Frank C
authors.initials: FC
authors.lastname: Brosius
mesh_terms: 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
chemical_list: 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