Geschlechtsabhängige Expression renaler und hepatischer Transporter für organische Anionen und Kationen
Sex-dependent expression of renal and hepatic organic anion and cation transporters
von Maja PD Dr. Henjakovic
Datum der mündl. Prüfung:2016-04-11
EnglischTransporter proteins of the solute carrier (SLC)- and ATP binding cassette (ABC)-gene family are responsible for the uptake and secretion of substances , e.g. therapeutic drugs. Clinic relevant renal SLC are the organic anion transporter 1 (OAT1), OAT3 and organic cation transporter 2 (OCT2) which take up drugs form the blood into the proximal tubule cell of the kidney. The ABC-transporter multidrug resistance-associated protein 2 (MRP2), MRP4 and multidrug resistance protein 1 are expressed in the liver and kidney and transport substances out of the cells. The expression of those transporters in healthy kidney and liver is sex differentially regulated, however the molecular mechanism is still unknown. The sex-dependent expression of renal transporters was shown in ZSF1-rats (a model for type 2 diabetes). The greatest difference was seen for Oat2 expression. The human OAT2 protein interacts with a high affinity to the loop-diuretic furosemide in vitro. In the liver of ZSF1-rats the mRNA amount of Oat3 and various enzymes involved in hepatic metabolism are sex-dependently expressed. We could show that the androgen-testosterone-complex does not influence the male-dominant expression of Oat1- and Oat3 transporters in rats. The transcription factor B-cell CLL/lymphoma 6 (BCL6) was identified as potential activator of Oat1 and Oat3. BCL6 activates the human OAT1 promoter, too. The BCL6 dependent transcriptional regulation was dependent on hepatocyte nuclear factor 1α (HNF1α). Since HNF1α influences promoter of various SLC- and ABC-transporters, the interaction of HNF1α and BCL6 with respect to their sex-dependent regulation needs to be further investigated. The sex-dependent transporter expression shall be taken into account in drug development and testing of new drugs.
Keywords: organic anion transporter; sex-different expression; OAT1; OAT2; OAT3; BCL6; HNF1α