OVEREXPRESSION OF TRANSFORMING GROWTH-FACTOR-BETA-1 MESSENGER-RNA IS ASSOCIATED WITH UP-REGULATION OF GLOMERULAR TENASCIN AND LAMININ GENE-EXPRESSION IN NONOBESE DIABETIC MICE

Nonobese diabetic (NOD) mice spontaneously develop immune-mediated ins ulin-dependent diabetes mellitus and nephropathy, providing an opportu nity to study the early molecular events in a model of diabetic glomer ulosclerosis. The expression of several genes coding for growth factor s and extracellular matrix was examined in microdissected glomeruli, b y the use of reverse transcription-competitive polymerase chain reacti on, in diabetic NOD mice (mean duration of diabetes, 28.5 +/- 7 days) and age-matched nondiabetic NOD mice with normal glucose tolerance. Th e levels of mRNA coding for transforming growth factor-beta 1, tenasci n, and laminin B1 increased 1.9-, 2.0-, and 1.7-fold, respectively, wh ereas platelet-derived growth factor (PDGF)-B, alpha 1(IV) collagen, 7 2-kd collagenase, alpha-smooth muscle actin, and beta-actin mRNA remai ned stable in the diabetic mice. The kidney advanced glycosylation end products levels increased 2.1-fold in the diabetic mice, and the diabe tic glomeruli showed an accumulation of tenascin and laminin but not o f type IV collagen by immunofluorescence microscopy. There was no incr ease in cell number per glomerulus after the onset of diabetes, a find ing consistent with stable PDGF-B and alpha-smooth muscle actin mRNA l evels. These findings provide evidence that increased glomerular trans forming growth factor-beta 1, but not PDGF-B, mRNA is associated with the up-regulation of tenascin and laminin expression after advanced gl ycosylation endproduct accumulation, early after the onset of diabetes .