Biological responses to PDGF-BB versus PDGF-DD in human mesangial cells
Biological responses to PDGF-BB versus PDGF-DD in human mesangial cells
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DOI：
10.1038/sj.ki.5000332
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发表时间：
2006-04-01
影响因子：
19.6
通讯作者：
Floege, J
中科院分区：
文献类型：
--
作者：
van Roeyen, CRC;Ostendorf, T;Floege, J
血小板衍生生长因子（PDGF）-BB和PDGF-DD介导体外和体内系膜细胞增殖。虽然PDGF-BB是PDGF α-和β-受体链的配体，但PDGF-DD更选择性地结合β-链，表明生物活性的潜在差异。在表达PDGF α-和β-受体亚单位的原代人肾小球系膜细胞（HMCs）中，比较了PDGF-BB和- DD诱导的信号转导和基因表达调控。所使用的生长因子浓度是基于它们在诱导HMC增殖和与β β-受体结合方面的等效性来选择的。这两种生长因子，虽然在不同的浓度诱导磷酸化和细胞外信号调节激酶1（ERK 1）和ERK 2的激活。此外，PDGF导致信号转导和转录激活因子1（STAT 1）和STAT 3的磷酸化和激活。PDGF-BB或- DD诱导的HMCs增殖可被丝裂原活化蛋白激酶-、Janus激酶（JAK）/STAT-或磷脂酰肌醇3-激酶途径的信号转导抑制剂阻断。使用基因芯片阵列和随后的实时逆转录酶（RT）-聚合酶链反应的验证，我们发现，在HMC的基质金属蛋白酶13（MMP-13）和MMP-14的基因，并在较低程度上，细胞色素B5和组织蛋白酶L的PDGF-BB专门调节，而没有专门的基因调控PDGF-DD检测。然而，在蛋白质水平上，MMP-13和-14都被PDGF-BB和- DD同等地诱导。PDGF-BB和PDGF-DD在HMC中产生相似的生物学应答，尽管效力不同。罕见的明显差异的基因调控没有导致不同的蛋白质表达，这表明在HMCs中，两种PDGF几乎完全通过PDGF β受体发挥其生物活性。
Platelet-derived growth factor ( PDGF)-BB and PDGF-DD mediate mesangial cell proliferation in vitro and in vivo. While PDGF-BB is a ligand for the PDGF alpha- and beta-receptor chains, PDGF-DD binds more selectively to the beta-chain, suggesting potential differences in the biological activities. Signal transduction and regulation of gene expression induced by PDGF-BB and - DD were compared in primary human mesangial cells (HMCs), which expressed PDGF a- and beta-receptor subunits. The growth factor concentrations used were chosen based on their equipotency in inducing HMCs proliferation and binding to the beta beta-receptor. Both growth factors, albeit at different concentrations induced phosphorylation and activation of extracellular signal-regulated kinase 1 (ERK1) and ERK2. In addition, PDGFs led to the phosphorylation and activation of signal transducers and activators of transcription 1 (STAT1) and STAT3. HMCs proliferation induced by either PDGF-BB or - DD could be blocked by signal transduction inhibitors of the mitogen-activated protein kinase-, Janus kinase (JAK)/STAT-, or phosphatidyl-inositol 3-kinase pathways. Using a gene chip array and subsequent verification by real-time reverse transcriptase (RT)-polymerase chain reaction, we found that in HMC genes for matrix metalloproteinase 13 (MMP-13) and MMP-14 and, to a low extent, cytochrome B5 and cathepsin L were exclusively regulated by PDGF-BB, whereas no exclusive gene regulation was detected by PDGF-DD. However, at the protein level, both MMP-13 and - 14 were equally induced by PDGF-BB and - DD. PDGF-BB and - DD effect similar biological responses in HMCs albeit at different potencies. Rare apparently differential gene regulation did not result in different protein expression, suggesting that in HMCs both PDGFs exert their biological activity almost exclusively via the PDGF beta-receptor.