Gilbert R E, Cox A, Wu L L, Allen T J, Hulthen U L, Jerums G, Cooper M E
Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia.
Diabetes. 1998 Mar;47(3):414-22. doi: 10.2337/diabetes.47.3.414.
Transforming growth factor-beta (TGF-beta) and the renin-angiotensin system (RAS) have both been implicated in the pathogenesis of glomerulosclerosis in diabetic kidney disease. However, tubulointerstitial pathology may also be an important determinant of progressive renal dysfunction in diabetic nephropathy. In the present study, we investigated tubulointerstitial injury, TGF-beta1 expression, and the effect of blocking the RAS by inhibition of ACE. We randomized 36 male SD rats to control and diabetic groups. Diabetes was induced in 24 rats by administration of streptozotocin; 12 diabetic rats were further randomized to receive the ACE inhibitor ramipril (3 mg/l drinking water). At 6 months, experimental diabetes was associated with tubulointerstitial damage, a 70% increase in expression of TGF-beta1 (P < 0.05 vs. control), and a 120% increase in alpha1 (IV) collagen gene expression (P < 0.01 vs. control). In situ hybridization demonstrated a diffuse increase in both TGF-beta1 and alpha1 (IV) collagen mRNA in renal tubules. In addition, intense expression of both transcripts was noted in regions of focal tubular dilatation. Administration of the ACE inhibitor ramipril prevented tubulointerstitial injury and the overexpression of TGF-beta1 and alpha1 (IV) collagen mRNA. Changes in gene expression were accompanied by parallel changes in immunostaining for TGF-beta1 and type IV collagen. The observed beneficial effects of ramipril on the tubulointerstitium in experimental diabetes suggest that this mechanism may contribute to the therapeutic effect of ACE inhibitors in diabetic nephropathy.
转化生长因子-β（TGF-β）和肾素-血管紧张素系统（RAS）均与糖尿病肾病肾小球硬化的发病机制有关。然而，肾小管间质病变也可能是糖尿病肾病进行性肾功能不全的重要决定因素。在本研究中，我们调查了肾小管间质损伤、TGF-β1表达以及通过抑制ACE阻断RAS的作用。我们将36只雄性SD大鼠随机分为对照组和糖尿病组。通过给予链脲佐菌素诱导24只大鼠患糖尿病；12只糖尿病大鼠进一步随机分组，接受ACE抑制剂雷米普利（3mg/l饮水）。6个月时，实验性糖尿病与肾小管间质损伤、TGF-β1表达增加70%（与对照组相比，P<0.05）以及α1（IV）胶原基因表达增加120%（与对照组相比，P<0.01）相关。原位杂交显示肾小管中TGF-β1和α1（IV）胶原mRNA均弥漫性增加。此外，在局灶性肾小管扩张区域观察到两种转录本的强烈表达。给予ACE抑制剂雷米普利可预防肾小管间质损伤以及TGF-β1和α1（IV）胶原mRNA的过度表达。基因表达的变化伴随着TGF-β1和IV型胶原免疫染色的平行变化。雷米普利对实验性糖尿病肾小管间质的有益作用表明，该机制可能有助于ACE抑制剂对糖尿病肾病的治疗效果。
