Stimulation of TGF-beta type II receptor by high glucose in mouse mesangial cells and in diabetic kidney.
Transforming growth factor-beta (TGF-beta) is important in the pathogenesis of diabetic nephropathy, but little is known about the regulation of the ligand-binding TGF-beta type II signaling receptor (TbetaIIR). There were significant increases in TbetaIIR protein and mRNA levels in kidney cortex after 1-6 wk of streptozotocin-induced diabetes. Mouse mesangial cells cultured in high glucose demonstrated significantly increased TbetaIIR protein and mRNA levels compared with normal glucose. This effect was independent of stimulation of TGF-beta bioactivity by high glucose. Consistent with transcriptional activation by high glucose, the half-life ( approximately 4 h) of TbetaIIR mRNA was not affected by glucose concentration. Moreover, mouse mesangial cells transiently transfected with reporter constructs containing the first 47- or 274-bp promoter fragments of TbetaIIR demonstrated significantly increased reporter activity in high glucose. Cells grown in high glucose demonstrated increased responsiveness to a relatively small dose of exogenous TGF-beta(1) (0.5 ng/ml): [(3)H]proline incorporation and alpha(1)(IV) collagen mRNA were significantly greater in cells cultured in high than in normal glucose. Hence, the expression of TbetaIIR is increased in the diabetic kidney and in mesangial cells cultured in high glucose, primarily because of stimulation of gene transcription. TbetaIIR upregulation by high ambient glucose may contribute to the increased sensitivity of mesangial cells to the profibrogenic action of TGF-beta(1).
Isono
M
M
Renal-Electrolyte and Hypertension Division, Department of Medicine, and Penn Center for the Molecular Studies of Kidney Diseases, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6144, USA.
Mogyorósi
A
A
Han
D C
DC
Hoffman
B B
BB
Ziyadeh
F N
FN
D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011392:Proline / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D003094:Collagen; D011392:Proline; D005947:Glucose