Glucose transporters control gene expression of aldose reductase, PKCalpha, and GLUT1 in mesangial cells in vitro.
The process linking increased glucose utilization and activation of metabolic pathways leading to end-organ damage from diabetes is not known. We have previously described rat mesangial cells that were transduced to constitutively express the facilitative glucose transporter 1 (GLUT1, MCGT1 cells) or bacterial beta-galactosidase (MCLacZ, control cells). Glucose transport was rate limiting for extracellular matrix production in the MCGT1 cells. In the present work, we investigated the effect of GLUT1 overexpression in mesangial cells on aldose reductase (AR), protein kinase Calpha (PKCalpha), and native GLUT1 transcript levels, to determine whether changes in GLUT1 alone could regulate their expression in the absence of high extracellular glucose concentrations. MCGT1 cells grown in normal (8 mM) or elevated (20 mM) glucose had elevated abundance of AR, PKCalpha, and the native GLUT1 transcripts compared with control cells. AR protein levels, AR activity, sorbitol production, and PKCalpha protein content were also greater in the MCGT1 cells than in control cells grown in the same media. This is the first report of the concomitant activation of AR, PKCalpha, and GLUT1 genes by enhanced GLUT1 expression. We conclude that increased GLUT1 expression leads to a positive feedback of greater GLUT1 expression, increased AR expression and activity with polyol accumulation, and increased total and active PKCalpha protein levels, which leads to detrimental stimulation of matrix protein synthesis by diabetic mesangial cells.
Department of Physiology, Division of Pediatric Endocrinology, College of Human Medicine, Michigan State University, East Lansing, Michigan 48824-1101, USA.
D N
DN
Henry
J V
JV
Busik
F C
FC
Brosius
C W
CW
Heilig
D000449:Aldehyde Reductase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D005920:Glomerular Mesangium / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats
D051272:Glucose Transporter Type 1; D007527:Isoenzymes; D009004:Monosaccharide Transport Proteins; D012333:RNA, Messenger; C495679:Slc2a1 protein, rat; D000449:Aldehyde Reductase; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D005947:Glucose