Park I S, Kiyomoto H, Abboud S L, Abboud H E
Department of Medicine, University of Texas Health Science Center at San Antonio 78284-7882, USA.
Diabetes. 1997 Mar;46(3):473-80. doi: 10.2337/diab.46.3.473.
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.
I型糖尿病肾病的最早表现包括系膜基质扩张、基底膜增厚和肾脏肥大。转化生长因子（TGF）-β是基质蛋白合成的强效诱导剂，是介导糖尿病中观察到的肾小球变化的主要候选因子。然而，糖尿病肾病早期TGF-β和基质蛋白的时间表达尚未明确界定。我们运用原位杂交和免疫组化技术，测定了链脲佐菌素（STZ）给药后3天、7天和14天糖尿病大鼠肾小球和间质中TGF-β及IV型胶原mRNA和蛋白的表达。早在糖尿病诱导后3天，肾小球和肾小管间质细胞中TGF-β和α1（IV）前胶原mRNA的表达就显著增加，这种效应持续了14天。在每个时间点还观察到TGF-β和IV型胶原蛋白的相应增加。胰岛素治疗显著抑制了TGF-β和IV型胶原mRNA及蛋白表达的增加。我们得出结论，在糖尿病快速肾脏生长的早期阶段，肾小球中TGF-β增加。这些发现表明，TGF-β可能是参与基底膜增厚和细胞外基质积聚发病机制的关键因素。胰岛素治疗对TGF-β和IV型胶原表达的抑制表明，它们可能是确定早期糖尿病肾病治疗干预效果的有用结构标志物。
