Lysophosphatidic Acid Increases Proximal Tubule Cell Secretion of Profibrotic Cytokines PDGF-B and CTGF through LPA2-and Gαq-Mediated Rho and αvβ6 Integrin-Dependent Activation of TGF-β
Lysophosphatidic Acid Increases Proximal Tubule Cell Secretion of Profibrotic Cytokines PDGF-B and CTGF through LPA2-and Gαq-Mediated Rho and αvβ6 Integrin-Dependent Activation of TGF-β
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DOI：
10.1016/j.ajpath.2012.06.035
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发表时间：
2012-10-01
影响因子：
6
通讯作者：
Venkatachalam, Manjeri A.
中科院分区：
文献类型：
--
作者：
Geng, Hui;Lan, Rongpei;Venkatachalam, Manjeri A.
缺血再灌注损伤（IRI）后，肾小管显示tgf - β信号被激活，促纤维化肽、血小板源性生长因子-b （PDGF-B）和结缔组织生长因子（CTGF）的表达增加。如果IRI后的小管修复不完全，这些肽的持续旁分泌活性可以激活间质成纤维细胞祖细胞并引起纤维化。我们发现，溶血磷脂酸（LPA）是一种普遍存在的磷脂，在损伤和炎症部位增加，通过培养的近端小管细胞的LPA2受体和G α q蛋白发出信号，以Rho/Rho激酶和α v β 6整合素依赖的方式反激活潜伏的tgf - β。活性tgf - β肽启动信号传导，增加PDGF-B和CTGF的产生和分泌。在IRI大鼠模型中，在再灌注早期开始的tgf - β信号的增加在恢复过程中没有消退，而是逐渐增加，导致小管间质纤维化。这伴随着LPA2和136整合素蛋白的相应增加，以及tgf - β 1、PDGF-B和CTGF的小管表达升高。使用药理tgf - β I型受体拮抗剂治疗可抑制tgf - β信号，降低β 6整合素、PDGF-B和CTGF的表达，并改善纤维化。我们认为lpa启动的自分泌信号是损伤肾小管细胞产生旁分泌促纤维化信号的潜在重要机制。（中华病理学杂志，2012,181:1236-1249;http://dx.doi.org/10.1016/j.ajpath.2012.06.035）
After ischemia-reperfusion injury (IRI), kidney tubules show activated transforming growth factor beta (TGF-beta) signaling and increased expression of profibrotic peptides, platelet-derived growth factor-B (PDGF-B) and connective tissue growth factor (CTGF). If tubule repair after IRI is incomplete, sustained paracrine activity of these peptides can activate interstitial fibroblast progenitors and cause fibrosis. We show that lysophosphatidic acid (LPA), a ubiquitous phospholipid that is increased at sites of injury and inflammation, signals through LPA2 receptors and G alpha q proteins of cultured proximal tubule cells to transactivate latent TGF-beta in a Rho/Rho-kinase and alpha v beta 6 integrin-dependent manner. Active TGF-beta peptide then initiates signaling to increase the production and secretion of PDGF-B and CTGF. In a rat model of IRI, increased TGF-beta signaling that was initiated early during reperfusion did not subside during recovery, but progressively increased, causing tubulointerstitial fibrosis. This was accompanied by correspondingly increased LPA2 and 136 integrin proteins and elevated tubule expression of TGF-beta 1, together with PDGF-B and CTGF. Treatment with a pharmacological TGF-beta type I receptor antagonist suppressed TGF-beta signaling, decreased the expression of beta 6 integrin, PDGF-B, and CTGF, and ameliorated fibrosis. We suggest that LPA-initiated autocrine signaling is a potentially important mechanism that gives rise to paracrine profibrotic signaling in injured kidney tubule cells. (Am J Pathol 2012, 181:1236-1249; http://dx.doi.org/10.1016/j.ajpath.2012.06.035)