Expression of transforming growth factor-beta and type IV collagen in early streptozotocin-induced diabetes.
The earliest manifestations of type I diabetic nephropathy include mesangial matrix expansion, basement membrane thickening, and renal hypertrophy. Transforming growth factor (TGF)-beta, a potent inducer of matrix 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 nephropathy has not been clearly defined. Using in situ hybridization and immunohistochemistry, we determined the expression of TGF-beta and type IV collagen mRNAs and proteins in glomeruli and interstitium of diabetic rats 3, 7, and 14 days after streptozotocin (STZ) administration. There was a marked increase in the expression of TGF-beta and alpha1(IV) procollagen mRNAs in glomerular and tubulointerstitial cells as early as 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 mRNAs and proteins. We conclude that TGF-beta is increased in glomeruli during the early phase of rapid renal growth in diabetes. These findings suggest that TGF-beta may be a key factor involved in the pathogenesis of basement membrane thickening and extracellular matrix accumulation. Inhibition of TGF-beta and type IV collagen expression by insulin treatment suggests that they may be useful structural markers for determining the efficacy of therapeutic intervention during early diabetic nephropathy.
Park
I S
IS
Department of Medicine, University of Texas Health Science Center at San Antonio 78284-7882, USA.
Kiyomoto
H
H
Abboud
S L
SL
Abboud
H E
HE
D000818:Animals; D001835:Body Weight; D003094:Collagen / Q000096:biosynthesis*; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000473:pathology / Q000503:physiopathology; D006984:Hypertrophy; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D008297:Male; D009929:Organ Size; D011347:Procollagen / Q000096:biosynthesis; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*
D011347:Procollagen; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D003094:Collagen