Interaction of MAPK and 12-lipoxygenase pathways in growth and matrix protein expression in mesangial cells
Interaction of MAPK and 12-lipoxygenase pathways in growth and matrix protein expression in mesangial cells
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DOI：
10.1152/ajprenal.00181.2002
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发表时间：
2002-11-01
影响因子：
4.2
通讯作者：
Natarajan, R
中科院分区：
文献类型：
--
作者：
Reddy, MA;Adler, SG;Natarajan, R
花生四烯酸代谢的脂氧合酶 (LO) 途径和丝裂原激活蛋白激酶 (MAPK) 可介导血管平滑肌细胞中的细胞生长和 ANG II 效应。然而，它们在肾系膜细胞（MC）中的作用尚不十分清楚。 ANG II 治疗大鼠 MC 显着增加 12-LO mRNA 表达和 12-LO 产物 12(S)-羟基二十碳四烯酸 [12(S)-HETE； P<0.03]。 ANG II 诱导的 [H-3] 亮氨酸掺入被 LO 抑制剂肉桂基-3,4-二羟基-α-氰基肉桂酸酯阻断 (P < 0.02)。 12(S)-HETE 和 ANG II 直接诱导细胞肥大和纤连蛋白 (FN) 表达 (P < 0.01)，程度相似。 ANG II 和 12(S)-HETE 导致 p38(MAPK) 及其靶转录因子 cAMP 反应元件结合蛋白 (CREB) 的激活。 p38(MAPK) 抑制剂 SB202190 阻断 ANG II-和 12(S)-HETE 诱导的 CREB 激活和 [H-3] 亮氨酸掺入。大鼠 12-LO mRNA 的特异性分子抑制剂，即一种新型核酶，可以减弱 ANG II 诱导的 FN mRNA。因此，p38(MAPK)依赖性CREB激活可能介导大鼠MC中ANG II和LO产物诱导的FN表达和细胞生长。 ANG II 效应可能由 LO 途径介导。这些结果表明，在与肾脏并发症相关的 MC 基质合成中，LO 和 p38(MAPK) 激活之间存在新的相互作用。
The lipoxygenase (LO) pathway of arachidonate metabolism and mitogen-activated protein kinases (MAPKs) can mediate cellular growth and ANG II effects in vascular smooth muscle cells. However, their role in renal mesangial cells (MC) is not very clear. ANG II treatment of rat MC significantly increased 12-LO mRNA expression and formation of the 12-LO product 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE; P < 0.03]. ANG II-induced [H-3] leucine incorporation was blocked by an LO inhibitor, cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (P < 0.02). 12(S)-HETE and ANG II directly induced cellular hypertrophy and fibronectin (FN) expression (P < 0.01) to a similar extent. ANG II and 12(S)-HETE led to activation of p38(MAPK) and its target transcription factor cAMP-responsive element-binding protein (CREB). ANG II- and 12(S)-HETE-induced CREB activation and [H-3] leucine incorporation were blocked by the p38(MAPK) inhibitor SB202190. A specific molecular inhibitor of rat 12-LO mRNA, namely, a novel ribozyme, could attenuate ANG II- induced FN mRNA. Thus p38(MAPK)-dependent CREB activation may mediate ANG II- and LO product-induced FN expression and cellular growth in rat MC. ANG II effects may be mediated by the LO pathway. These results suggest a novel interaction between LO and p38(MAPK) activation in MC matrix synthesis associated with renal complications.