Sex-dependent expression of renal (and hepatic) organic anion transporters

在该项目的前一个资助期（Bu 571/8-1），我们研究了性别依赖性有机阴离子转运蛋白1（Oat 1/OAT 1）和3（Oat 3/OAT 3）表达的转录调控。我们发现，雄激素受体-睾酮复合物不直接调节大鼠肾脏中Oat 1和Oat 3的性别依赖性表达。该项目令人惊讶且迄今未知的发现是大鼠肾脏中转录因子B细胞CLL /淋巴瘤6（BCL 6）的男性主导表达以及BCL 6介导的Oat 1/OAT 1和Oat 3/OAT 3启动子的激活。因此，转录因子BCL 6可能与大鼠和人类肾脏中这些转运蛋白的性别依赖性调节有关。我们的研究结果间接表明BCL 6介导的启动子激活Oat 1/OAT 1和Oat 3/OAT 3。我们假设已知的肾脏和肝脏转运系统的激活剂，如肝细胞核因子1-α（HNF 1A）参与BCL 6介导的这些启动子的调节。在拟议的项目中，我们希望确定BCL 6诱导Oat 1/OAT 1和Oat 3/OAT 3激活的分子机制。此外，我们还想分析肾脏和肝脏细胞系统中OAT 4、URAT 1、OAT 2、OAT 5和OAT 7的性别依赖性启动子激活。首先，应检测BCL 6、雄激素受体/睾酮和雌激素受体/雌激素对OAT 4、URAT 1、OAT 2、OAT 5和OAT 7启动子激活的影响。其次，我们想研究这些调节系统对肝脏转运蛋白OAT 2、OAT 5和OAT 7的内源性蛋白表达的影响。

In the previous funding period of this project (Bu571/8-1), we investigated the transcriptional regulation of sex-dependent organic anion transporter 1 (Oat1/OAT1) and 3 (Oat3/OAT3) expression. We showed that the androgen receptor-testosterone complex does not directly regulate sex-dependent expression of Oat1 and Oat3 in rat kidneys. Surprising and so far unknown findings of the project were the male-dominant expression of transcription factor B-cell CLL / lymphoma 6 (BCL6) in rat kidneys and the BCL6-mediated activation of Oat1/OAT1 and Oat3/OAT3 promoters. Therefore, the transcription factor BCL6 is possibly implicated in the sex-dependent regulation of these transport proteins in rat and human kidneys. Our results indicate indirectly BCL6-mediated promoter activation of Oat1/OAT1 and Oat3/OAT3. We assume that known activators of renal and hepatic transport systems, such as hepatocyte nuclear factor 1-alpha (HNF1A) are involved in the BCL6-mediated regulation of these promoters. In the proposed project, we want to identify the molecular mechanism by which BCL6 induces the activation of Oat1/OAT1 and Oat3/OAT3. In addition, we want to analyze the sex-dependent promoter activation of OAT4, URAT1, OAT2, OAT5 and OAT7 in renal and hepatic cell systems. First, the effects of BCL6, androgen receptor / testosterone and the estrogen receptor / estrogen on the promoter activation of OAT4, URAT1, OAT2, OAT5 and OAT7 shall be tested. Secondly, we want to investigate the impact of these regulatory systems on endogenous protein expression of the hepatic transporters OAT2, OAT5 and OAT7.