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

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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.