Signaling pathways and late-onset gene induction associated with renal mesangial cell hypertrophy
Signaling pathways and late-onset gene induction associated with renal mesangial cell hypertrophy
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DOI：
10.1093/emboj/cdf535
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发表时间：
2002-10-15
期刊：
影响因子：
11.4
通讯作者：
Kyriakis, JM
中科院分区：
文献类型：
--
作者：
Goruppi, S;Bonventre, JV;Kyriakis, JM
在糖尿病等慢性疾病中，持续的应激刺激引发细胞功能和基因表达的持续、自我强化的重编程，最终导致病理状态。基因表达的迟发性稳定变化是理解慢性疾病分子基础的关键。肾衰竭是糖尿病的常见并发症，但了解甚少。糖尿病肾病开始于肾小球系膜细胞肥大和增生，结合过量基质沉积。血管活性肽内皮素促进糖尿病肾病系膜细胞肥大。在这项研究中，我们研究了内皮素诱导的系膜细胞肥大所需的信号通路和基因表达的变化。转录谱确定了七个基因诱导内皮素的缓慢动力学。其中，编码小的碱性螺旋-环-螺旋蛋白的p8被最强烈且稳定地诱导。p8在糖尿病肾脏中也被诱导。肾小球系膜细胞肥大和p8诱导都需要ERK、JNK/SAPK和PI-3-K通路的激活。小干扰RNA（siRNA）介导的RNA干扰表明，p8是内皮素诱导的肥大所必需的。因此，p8是糖尿病肾肥大的新标志物。
In chronic diseases such as diabetes mellitus, continuous stress stimuli trigger a persistent, self-reinforcing reprogramming of cellular function and gene expression that culminates in the pathological state. Late-onset, stable changes in gene expression hold the key to understanding the molecular basis of chronic diseases. Renal failure is a common, but poorly understood complication of diabetes. Diabetic nephropathy begins with mesangial cell hypertrophy and hyperplasia, combined with excess matrix deposition. The vasoactive peptide endothelin promotes the mesangial cell hypertophy characteristic of diabetic nephropathy. In this study, we examined the signaling pathways and changes in gene expression required for endothelin-induced mesangial cell hypertrophy. Transcriptional profiling identified seven genes induced with slow kinetics by endothelin. Of these, p8, which encodes a small basic helix-loop-helix protein, was most strongly and stably induced. p8 is also induced in diabetic kidney. Mesangial cell hypertrophy and p8 induction both require activation of the ERK, JNK/SAPK and PI-3-K pathways. Small interfering RNA (siRNA)-mediated RNA interference indicates that p8 is required for endothelin-induced hypertrophy. Thus, p8 is a novel marker for diabetic renal hypertrophy.