D-glucose stimulates mesangial cell GLUT1 expression and basal and IGF-I-sensitive glucose uptake in rat mesangial cells: implications for diabetic nephropathy.
The complications of diabetes arise in part from abnormally high cellular glucose uptake and metabolism. To determine whether altered glucose transporter expression may be involved in the pathogenesis of diabetic nephropathy, we investigated the effects of elevated extracellular glucose concentrations on facilitative glucose transporter (GLUT) expression in rat mesangial cells. GLUT1 was the only transporter isoform detected. Cells exposed to 20 mmol/l glucose medium for 3 days demonstrated increases in GLUT1 mRNA (134%, P < 0.002), GLUT1 protein (68%, P < 0.02), and V(max) (50%, P < 0.05) for uptake of the glucose analog [3H]2-deoxyglucose (3H2-DOG), when compared to cells chronically adapted to physiologic glucose concentrations (8 mmol/l). The increase in GLUT1 protein was sustained at 3 months, the latest time point tested (77% above control, P < 0.01). In contrast, hypertonic mannitol had no effect on GLUT1 protein levels. Insulin-like growth factor I (IGF-I; 30 ng/ml) increased the uptake of 3H2-DOG by 28% in 8 mmol/l glucose-treated cells (P < 0.05) and by 75% in cells switched to 20 mmol/l glucose for 3 days (P < 0.005). These increases in 3H2-DOG uptake occurred despite a lack of effect of IGF-I on GLUT1 protein levels (P > 0.5 vs. control). Therefore, hyperglycemia and IGF-I treatment both lead to increases in mesangial cell glucose uptake, and hyperglycemia induces increased GLUT1 expression, which can directly lead to the pathological changes of diabetic nephropathy. The effects of high glucose and of IGF-I to stimulate 3H2-DOG uptake also appear to be additive.
Heilig
C W
CW
Department of Medicine, Henry Ford Hospital, Detroit, Michigan, USA.
Liu
Y
Y
England
R L
RL
Freytag
S O
SO
Gilbert
J D
JD
Heilig
K O
KO
Zhu
M
M
Concepcion
L A
LA
Brosius
F C
FC
D000818:Animals; D015152:Blotting, Northern; D002461:Cell Line, Transformed; D003847:Deoxyglucose / Q000032:analysis / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000209:etiology*; D004305:Dose-Response Relationship, Drug; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology*; D051272:Glucose Transporter Type 1; D015151:Immunoblotting; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D009004:Monosaccharide Transport Proteins / Q000032:analysis / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D014316:Tritium
D051272:Glucose Transporter Type 1; D009004:Monosaccharide Transport Proteins; D012333:RNA, Messenger; C495679:Slc2a1 protein, rat; D014316:Tritium; D007334:Insulin-Like Growth Factor I; D003847:Deoxyglucose; D005947:Glucose