Chen Yung-Ming, Chiang Wen-Chih, Yang Yalin, Lai Chun-Fu, Wu Kwan-Dun, Lin Shuei-Liong
Renal Division, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yun-Lin, Taiwan.
Mol Med. 2015 Apr 13;21(1):276-84. doi: 10.2119/molmed.2015.00023.
Anti-Thy1 glomerulonephritis is a rat nephritis model closely simulating human mesangial proliferative glomerulonephritis. It affects primarily the mesangium, yet displays substantial proteinuria during the course. This study investigated the molecular signals underlying proteinuria in this disease and the modulation of which by the known antiproteinuric agent, pentoxifylline. Male Wistar rats were randomly divided into a control group and nephritic groups with or without treatment with IMD-0354 (an IκB kinase inhibitor), SB431542 (an activin receptor-like kinase inhibitor) or pentoxifylline. Kidney sections were prepared for histological examinations. Glomeruli were isolated for mRNA and protein analysis. Urine samples were collected for protein and nephrin quantitation. One day after nephritis induction, proteinuria developed together with ultrastructural changes of the podocyte and downregulation of podocyte mRNA and protein expression. These were associated with upregulation of tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β/activins mRNAs and activation of nuclear factor (NF)-κB p65 and Smad2/3. IMD-0354 attenuated proteinuria on d 1, whereas SB431542 decreased proteinuria on d 3 and 5, in association with partial restoration of downregulated podocyte mRNA and protein expression. Pentoxifylline attenuated proteinuria and nephrinuria through the course, plus inhibition of p-NF-κB p65 (d 1) and p-Smad2/3 (d 5) and partial reversal of downregulated podocyte mRNA and protein. Our data show that the pathogenesis of proteinuria in anti-Thy1 glomerulonephritis involves TNF-α and TGF-β/activin pathways, and the evolution of this process can be attenuated by pentoxifylline via downregulation of NF-κB and Smad signals and restoration of the podocyte component of the glomerular filtration barrier.
抗 Thy1 肾小球肾炎是一种与人类系膜增生性肾小球肾炎极为相似的大鼠肾炎模型。它主要影响系膜，但在病程中会出现大量蛋白尿。本研究探讨了该疾病中蛋白尿产生的分子信号以及已知的抗蛋白尿药物己酮可可碱对其的调节作用。雄性 Wistar 大鼠被随机分为对照组以及接受或未接受 IMD - 0354（一种 IκB 激酶抑制剂）、SB431542（一种激活素受体样激酶抑制剂）或己酮可可碱治疗的肾炎组。制备肾脏切片用于组织学检查。分离肾小球用于 mRNA 和蛋白质分析。收集尿液样本进行蛋白质和 nephrin 定量。肾炎诱导后一天，蛋白尿出现，同时足细胞发生超微结构改变，足细胞 mRNA 和蛋白质表达下调。这些变化与肿瘤坏死因子（TNF）-α 和转化生长因子（TGF）-β/激活素 mRNA 的上调以及核因子（NF）-κB p65 和 Smad2/3 的激活有关。IMD - 0354 在第 1 天减轻了蛋白尿，而 SB431542 在第 3 天和第 5 天降低了蛋白尿，同时下调的足细胞 mRNA 和蛋白质表达部分恢复。己酮可可碱在整个病程中减轻了蛋白尿和 nephrinuria，同时抑制了 p - NF -κB p65（第 1 天）和 p - Smad2/3（第 5 天），并部分逆转了下调的足细胞 mRNA 和蛋白质表达。我们的数据表明，抗 Thy1 肾小球肾炎中蛋白尿的发病机制涉及 TNF -α 和 TGF -β/激活素途径，己酮可可碱可通过下调 NF -κB 和 Smad 信号以及恢复肾小球滤过屏障的足细胞成分来减轻这一过程的进展。
