Prostaglandin E2 stimulates expression of osmoprotective genes in MDCK cells and promotes survival under hypertonic conditions
Prostaglandin E2 stimulates expression of osmoprotective genes in MDCK cells and promotes survival under hypertonic conditions
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DOI：
10.1113/jphysiol.2007.135178
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发表时间：
2007-08-15
影响因子：
5.5
通讯作者：
Beck, Franz-X
中科院分区：
文献类型：
--
作者：
Neuhofer, Wolfgang;Steinert, Daniela;Beck, Franz-X
肾髓质细胞通过环氧合酶 (COX)-1 和 -2 产生大量前列腺素 E-2 (PGE(2))。众所周知，PGE(2) 在盐和水平衡以及维持髓质血流方面发挥着关键作用。由于肾髓质 PGE(2) 的产生在抗利尿作用中增加，并且由于 COX 抑制与缺水期间肾髓质的损伤有关，因此 PGE(2) 可能会促进肾乳头细胞对高间质溶质浓度的适应。为了解决这个问题，在分析（i）细胞存活，（ii）渗透保护基因（AR，BGT1，SMIT，HSP70和COX-2）的表达，（iii）亚细胞TonEBP / NFAT5丰度，（iv）TonEBP / NFAT5转录活性和（v）醛糖还原酶启动子活性之前，MDCK细胞在存在或不存在20 mu M PGE（2）的情况下暴露于逐渐增加的张力。在 PGE(2) 存在下，提高培养基张力后的细胞存活率和细胞凋亡指数显着改善。 PGE(2) 显着增加张力介导的 AR、SMIT 和 HSP70 mRNA 上调。然而，核丰度和 TonEBP/NFAT5 驱动的报告基因活性均未被 PGE(2) 提高，但醛糖还原酶启动子活性却被 PGE(2) 显着提高。有趣的是，张力诱导的 COX-2 表达和活性也受到 PGE(2) 的刺激，表明存在正反馈循环。这些结果表明，主要的髓质前列腺素类 PGE(2) 刺激渗透保护基因的表达，并有利于髓质细胞适应增加的间质张力，这种效应不能直接用各个靶基因启动子区域中 TonE 的存在来解释。这些发现可能与镇痛药物相关的髓质损伤的病理生理学有关。
The cells of the renal medulla produce large amounts of prostaglandin E-2 (PGE(2)) via cyclooxygenases (COX)-1 and -2. PGE(2) is well known to play a critical role in salt and water balance and maintenance of medullary blood flow. Since renal medullary PGE(2) production increases in antidiuresis, and since COX inhibition is associated with damage to the renal medulla during water deprivation, PGE(2) may promote the adaptation of renal papillary cells to high interstitial solute concentrations. To address this question, MDCK cells were exposed to a gradual tonicity increase in the presence or absence of 20 mu M PGE(2) prior to analysis of (i) cell survival, (ii) expression of osmoprotective genes (AR, BGT1, SMIT, HSP70 and COX-2), (iii) subcellular TonEBP/NFAT5 abundance, (iv) TonEBP/NFAT5 transcriptional activity and (v) aldose reductase promoter activity. Cell survival and apoptotic indices after raising the medium tonicity improved markedly in the presence of PGE(2). PGE(2) significantly increased tonicity-mediated up-regulation of AR, SMIT and HSP70 mRNAs. However, neither nuclear abundance nor TonEBP/NFAT5-driven reporter activity were elevated by PGE(2), but aldose reductase promoter activity was significantly increased by PGE(2). Interestingly, tonicity-induced COX-2 expression and activity was also stimulated by PGE(2), suggesting the existence of a positive feedback loop. These results demonstrate that the major medullary prostanoid, PGE(2), stimulates the expression of osmoprotective genes and favours the adaptation of medullary cells to increasing interstitial tonicities, an effect that is not explained directly by the presence of TonEs in the promoter region of the respective target genes. These findings may be relevant in the pathophysiology of medullary damage associated with analgesic drugs.