Connective tissue growth factor (CTGF) promotes activated mesangial cell survival via up-regulation of mitogen-activated protein kinase phosphatase-1 (MKP-1)
Connective tissue growth factor (CTGF) promotes activated mesangial cell survival via up-regulation of mitogen-activated protein kinase phosphatase-1 (MKP-1)
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DOI：
10.1042/bj20061817
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发表时间：
2007-08-15
影响因子：
4.1
通讯作者：
Mason, Roger M.
中科院分区：
文献类型：
--
作者：
Wahab, Nadia;Cox, Dimity;Mason, Roger M.
活化的系膜细胞被认为在慢性病理条件下，包括DN（糖尿病肾病）的肾纤维化的发展中起关键作用。它们的存活时间延长可能会促进疾病的发展，因为它们表达的生长因子和细胞外基质蛋白的量增加。结缔组织生长因子（CTGF）是由活化的系膜细胞产生的生长因子之一，在DN的发病机制中起关键作用。先前的研究表明，将外源性CTGF添加到HMC（人系膜细胞）中快速激活ERKI/2（细胞外信号调节激酶1/2）MAPK（促分裂原活化蛋白激酶）和INK（c-Jun N末端激酶）MAPK，但不激活p38 MAPK，尽管上游激酶MKK 3/6（MAPK激酶3/6）被激活。本研究的目的是调查是否缺乏磷酸化的p38 MAPK的CTGF对活化的HMCs具有抗凋亡作用。我们发现，在HMC CTGF诱导快速转录激活和MKP-1（MAPK磷酸酶-1），一个双特异性磷酸酶，去磷酸化p38 MAPK的合成。这反过来又防止了抗凋亡蛋白Bcl-2被磷酸化并失去其功能，从而导致细胞存活。在用CTGF处理的系膜细胞中，使用siRNA（小干扰RNA）或反义寡核苷酸敲除MKP-1蛋白，允许p38 MAPK活化并诱导系膜细胞死亡。
Activated mesangial cells are thought to play a pivotal role in the development of kidney fibrosis under chronic pathological conditions, including DN (diabetic nephropathy). Their prolonged survival may enhance the development of the disease since they express increased amounts of growth factors and extracellular matrix proteins. CTGF (connective tissue growth factor) is one of the growth factors produced by activated mesangial cells and is reported to play a key role in the pathogenesis of DN. Previous studies have shown that addition of exogenous CTGF to HMCs (human mesangial cells) rapidly activates ERKI/2 (extracellular-signal-regulated kinase 1/2) MAPK (mitogen-activated protein kinase) and INK (c-Jun N-terminal kinase) MAPK, but not the p38 MAPK, despite the activation of the upstream kinases, MKK3/6 (MAPK kinase 3/6). The aim of the present study was to investigate whether the lack of phosphorylated p38 MAPK by CTGF has an anti-apoptotic effect on activated HMCs. We show that in HMC CTGF induces the rapid transcriptional activation and synthesis of MKP-1 (MAPK phosphatase-1), a dual specificity phosphatase that dephosphorylates p38 MAPK. This in turn prevents the anti-apoptotic protein, Bcl-2, from being phosphorylated and losing its function, leading to the survival of the cells. Knockout of MKP-1 protein in mesangial cells treated with CTGF, using siRNA (small interfering RNA) or antisense oligonucleotides, allows p38 MAPK activation and induces mesangial cell death.