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

在本项目的前一个资助时期(Bu571/8-1)，我们研究了性别依赖的有机阴离子转运蛋白1(OAT1/OAT1)和3(OAT3/OAT3)的转录调控。我们发现，雄激素受体-睾酮复合体并不直接调节大鼠肾脏中OAT1和OAT3的性别依赖性表达。该项目令人惊讶且迄今未知的发现是转录因子B细胞CLL/淋巴瘤6(BCL6)在大鼠肾脏中的男性主导表达，以及BCL6介导的Oat1/OAT1和OAT3/OAT3启动子的激活。因此，转录因子BCL6可能参与了这些转运蛋白在大鼠和人类肾脏中的性别依赖性调节。我们的结果表明BCL6间接地介导了OAT1/OAT1和OAT3/OAT3启动子的激活。我们推测，已知的肾和肝转运系统的激活物，如肝细胞核因子1-α(HNF1A)参与了BCL6对这些启动子的调节。在拟议的项目中，我们想要确定BCL6诱导OAT1/OAT1和OAT3/OAT3激活的分子机制。此外，我们还想分析OAT4、URAT1、OAT2、OAT5和OAT7在肾和肝细胞系统中的性别依赖性启动子激活。首先，检测BCL6、雄激素受体/睾酮和雌激素受体/雌激素对OAT4、URAT1、OAT2、OAT5和OAT7启动子激活的影响。其次，我们想要研究这些调控系统对肝脏转运蛋白OAT2、OAT5和OAT7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.