Renal TGF-beta regulation in spontaneously diabetic NOD mice with correlations in mesangial cells.
Diabetic nephropathy is characterized by excessive glomerular matrix accumulation, basement membrane thickening and sclerosis. Although it is clear that systemic metabolic disturbances precipitate such renal changes, the signals and pathways involved in this process are not fully elucidated. Recent evidence suggests that growth factors/cytokines are intimately involved in the pathogenesis of diabetic nephropathy. Because of its prosclerotic properties, transforming growth factor-beta (TGF-beta) is a prime candidate mediator of diabetic nephrosclerosis. We examined perfused kidney tissues isolated from spontaneously diabetic, non-obese diabetic mice (NOD) for TGF-beta content. By using murine isotype specific TGF-beta probes, we demonstrate that within 5 to 10 days of hyperglycuria renal TGF-beta 2 mRNA and protein content increases. By immunohistochemical analysis, de novo TGF-beta immunoreactivity was detected within both glomeruli and the interstitium. In order to determine the signals involved in promoting kidney TGF-beta content in vivo, TGF-beta regulation was examined in renal mesangial cells in vitro. Murine mesangial cells stimulated with glycosylated protein secrete bioactive TGF-beta and demonstrate a disproportionate increase in the steady state levels of TGF-beta 2 mRNA. These data suggest that a major early renal response in NOD mice to hyperglycemia or to glycosylated proteins is characterized by increases in TGF-beta.
Pankewycz
O G
OG
Health Sciences Center, University of Virginia, Charlottesville.
Guan
J X
JX
Bolton
W K
WK
Gomez
A
A
Benedict
J F
JF
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism; D007124:Immunoenzyme Techniques; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D012333:RNA, Messenger / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta