Department of Molecular Physiology, College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu, Shiga, 525-8577, Japan,
Pflugers Arch. 2014 May;466(5):925-35. doi: 10.1007/s00424-013-1351-8. Epub 2013 Sep 21.
OAT-PG is a kidney-specific prostaglandin transporter and exclusively expressed at the basolateral membrane of proximal tubules in rodent kidneys. We previously reported that OAT-PG was dominantly expressed in the male kidney similar to the other SLC22 family proteins as organic anion transporter (OAT) 1 and OAT3. Recently, Wegner et al. revealed that a transcription factor, B-cell CLL/lymphoma 6 (BCL6), is associated with the male-dominant expressions of OAT1 and OAT3 in the rat kidney. Here, we performed the luciferase assay to investigate whether OAT-PG is also transcriptionally regulated by BCL6. However, the promoter activity of OAT-PG was not directly affected by BCL6 overexpression nor the testosterone treatment, suggesting that different regulatory mechanisms underlie the male-dominant transcriptional regulation of OAT-PG compared to those of OAT1 and OAT3. We newly found that adrenalectomy (Adx) of male rat caused a significant reduction of OAT-PG expression without any significant changes in the OAT1 and OAT3 expressions, and it was recovered by the dexamethasone administration. Furthermore, the renocortical PGE2 concentration was markedly increased in Adx male rat, concomitant with the downregulation of OAT-PG, and it was reduced to the basal level by dexamethasone treatment. In the luciferase assay, dexamethasone stimulated OAT-PG promoter activity but not OAT1. The luciferase activity responsiveness to dexamethasone was significantly reduced by the deletion of glucocorticoid response elements in the OAT-PG promoter region. These results suggest that glucocorticoid plays an important role in the regulation of the renocortical PGE2 concentration by the transcriptional regulation of OAT-PG in the rat kidney.
OAT-PG 是一种肾脏特异性的前列腺素转运体，仅在啮齿动物肾脏的近端肾小管基底外侧膜表达。我们之前报道过，OAT-PG 与其他 SLC22 家族蛋白（如有机阴离子转运体 1 和 OAT3）一样，在雄性肾脏中占主导地位表达。最近，Wegner 等人揭示转录因子 B 细胞 CLL/淋巴瘤 6（BCL6）与大鼠肾脏中 OAT1 和 OAT3 的雄性优势表达有关。在这里，我们进行了荧光素酶测定，以研究 OAT-PG 是否也受 BCL6 的转录调控。然而，OAT-PG 的启动子活性不受 BCL6 过表达或睾酮处理的直接影响，这表明与 OAT1 和 OAT3 相比，OAT-PG 的雄性优势转录调控存在不同的调节机制。我们新发现，雄性大鼠肾上腺切除术（Adx）导致 OAT-PG 表达显著减少，而 OAT1 和 OAT3 表达无明显变化，并用地塞米松处理后可恢复。此外，Adx 雄性大鼠的肾皮质 PGE2 浓度明显增加，同时 OAT-PG 下调，并用地塞米松处理后降至基础水平。在荧光素酶测定中，地塞米松刺激 OAT-PG 启动子活性，但不刺激 OAT1。OAT-PG 启动子区域中糖皮质激素反应元件缺失后，地塞米松对荧光素酶活性的反应性显著降低。这些结果表明，糖皮质激素在大鼠肾脏中通过 OAT-PG 的转录调控对肾皮质 PGE2 浓度的调节中起重要作用。
