Noh Hey-Jeong, Kim Hyun-Chul, Lee Sang-Sook, Kang Yu-Na, Chae Young-Mi, Park Kwan-Kyu
Department of Pathology, Keimyung University School of Medicine, Daegu, Korea.
J Korean Med Sci. 2006 Jun;21(3):430-5. doi: 10.3346/jkms.2006.21.3.430.
Diabetic nephropathy is characterized by an expansion of the glomerular mesangium, caused by mesangial cell proliferation and an excessive accumulation of extracellar matrix (ECM) proteins, which eventually leading to glomerulosclerosis. TGF-beta1 was found to play an important role in the accumulation of ECM in the kidney. In this study, TGF-beta1 RNA interference was used as an effective therapeutic strategy. The inhibitory effect of TGF-beta1 small interfering RNAs (siRNAs) on the high glucose-induced overexpression of TGF-beta1 in rat mesangial ceys (RMCs). A high levels of glucose induces TGF-beta1 mRNA and protein, and TGF-beta1 siRNAs reduce the ability of high glucose to stimulate their expression. We also examined the inhibitory effect of TGF-beta1 siRNAs on the expression of plasminogen activator inhibitor (PAI)-1 and Collagen Type I which are down-regulators of TGF-beta1. The expression of TGF-beta1, PAI-1 and Collagen Type I was increased in RMCs that were stimulated by 30 mM glucose. TGF-beta1 siRNAs reduces high glucose-induced TGF-beta1, PAI-1, and Collagen Type I mRNA and protein expression in a dose-dependent manner. In conclusion, the present study demonstrates that TGF-beta1 siRNAs effectively inhibits TGF-beta1 mRNA and protein expression in RMCs. These suggest that TGF-beta1 siRNAs through RNAi may be a useful tool for developing new therapeutic applications for the treatment of diabetic nephropathy.
糖尿病肾病的特征是肾小球系膜扩张，这是由系膜细胞增殖和细胞外基质（ECM）蛋白过度积累引起的，最终导致肾小球硬化。研究发现转化生长因子-β1（TGF-β1）在肾脏ECM积累中起重要作用。在本研究中，TGF-β1 RNA干扰被用作一种有效的治疗策略。TGF-β1小干扰RNA（siRNAs）对高糖诱导的大鼠系膜细胞（RMCs）中TGF-β1过表达的抑制作用。高糖水平诱导TGF-β1 mRNA和蛋白表达，而TGF-β1 siRNAs降低高糖刺激其表达的能力。我们还检测了TGF-β1 siRNAs对纤溶酶原激活物抑制剂（PAI）-1和I型胶原蛋白表达的抑制作用，它们是TGF-β1的下游调节因子。在30 mM葡萄糖刺激的RMCs中，TGF-β1、PAI-1和I型胶原蛋白的表达增加。TGF-β1 siRNAs以剂量依赖的方式降低高糖诱导的TGF-β1、PAI-1和I型胶原蛋白mRNA和蛋白表达。总之，本研究表明TGF-β1 siRNAs能有效抑制RMCs中TGF-β1 mRNA和蛋白表达。这些结果提示，通过RNA干扰的TGF-β1 siRNAs可能是开发糖尿病肾病新治疗应用的有用工具。
