EXPRESSION OF TRANSFORMING GROWTH-FACTOR-BETA AND TYPE-IV COLLAGEN INEARLY STREPTOZOTOCIN-INDUCED DIABETES

The earliest manifestations of type I diabetic nephropathy include mes angial matrix expansion, basement membrane thickening, and renal hyper trophy. Transforming growth factor (TGF)-beta, a potent inducer of mat rix protein synthesis, is a prime candidate to mediate the glomerular changes observed in diabetes. However, the temporal expression of TGF- beta and matrix proteins during the early stage of diabetic nephropath y has not been clearly defined. Using in situ hybridization and immuno histochemistry, we determined the expression of TGF-beta and type IV c ollagen mRNAs and proteins in glomeruli and interstitium of diabetic r ats 3, 7, and 14 days after streptozotocin (STZ) administration. There was a marked increase in the expression of TGF-beta and alpha 1(IV) p rocollagen mRNAs in glomerular and tubulointerstitial cells as early a s 3 days after induction of diabetes, an effect that persisted for 14 days. A concomitant increase in TGF-beta and type IV collagen proteins was also observed at each time point. Insulin treatment substantially inhibited the increased expression of TGF-beta and collagen type IV m RNAs and proteins. We conclude that TGF-beta is increased in glomeruli during the early phase of rapid renal growth in diabetes. These findi ngs suggest that TGF-beta may be a key factor involved in the pathogen esis of basement membrane thickening and extracellular matrix accumula tion. Inhibition of TGF-beta and type IV collagen expression by insuli n treatment suggests that they may be useful structural markers for de termining the efficacy of therapeutic intervention during early diabet ic nephropathy.