gerBiggemann, FrankGreven, JoachimRegulation des renalen Natrium-abhängigen Gallensäuren-Transporters (ASBT) durch Sexualhormone und Glukokortikoideinfo:eu-repo/classification/ddc/610TestosteronEthinylestradiolBuserelinDexamethasonTaurocholatMedizinASBTBuserelinICI 182780Frische Isolierung proximaler TubuluszellenClearanceWestern Blotethinylestradioltestosteronebuserelinedexamethasonetaurocholatefreshly isolated proximal tubular cellsclearance studiesThe bile acids filtered through the glomeruli nearly completely escape urinary excretion due to an effecient tubular reabsorption process, which help to conserve bile acids. Reabsorption is mediated by the sodium-dependent bile acid transporter (ASBT) localized in the apical brush border membrane of the proximal tubular cell. The aim of the present study was to assess whether the ASBT-mediated transport of the bile acid taurocholate is regulated by sex hormones or glucocorticoids. In-vitro uptake experiments with freshly isolated proximal tubular cells from female and male sprague-dawley rats and in-vivo clearance experiments were performed using the radioactive bile acid 3H-taurocholate as a substrate. Furthermore, western blot analyse were performed to determine the ASBT-protein amount. The uptake experiments with freshly isolated proximal tubular cells showed a high significant difference of the 3H-taurocholate accumulation ratio of 5.63 +/- 0.28 in male versus 3.68 +/- 0.43 in female animals (p<0,01). This gender difference of cellular taurocholate uptake was confirmed by the clearance studies, which showed a significant difference in 3H-taurocholate clearance of 133.9 +/- 28.1 in male and of 262.0 +/- 45.4 µl/min x 100 g body weight in female rats (p<0,05). Then treatment of female rats with testosterone (5 mg/kg body weight) only lead to a mild, not significant increase of intracellular taurocholate uptake. In contrast treatment of male rats with ethinylestradiol at a dose of 50 µg/kg body weight lead to a highly significant inhibition of 61.6 +/- 13.4% of the taurocholate accumulation ratio (p< 0.001). Neither surgical ovariectomy nor chemical castration with the GnRH- analog busereline (24 µg/day for 4 weeks) influenced taurocholate uptake of female rats. Futhermore treatment with the estrogen receptor antagonist ICI 182780 (Faslodex) of female rats (0.5 and 1.0 mg/kg body weight) showed no significant effect. However, application of ethinylestradiol (5 mg/kg body weight) to ovariectomised rats lead, as in normal male rats, to a significant inhibition of the taurocholate accumulation ratio of 53.7 +/- 15.8% (p<0.05). By determining bile acid serum levels we excluded, that this change was due to an ethinylestradiol induced cholestasis. The main finding of this study was a significant higher tubular taurocholate clearance and therefore less intracellular taurocholate accumulation in female compared to male rats. This gender-specific difference is likely to be due to an inhibitory effect of estrogens on the renal ASBT. Western blot analysis showed no difference in ASBT-protein amount suggesting a non-genomic mechanism. For glucocorticoids however, we could not demonstrate a regulatory effect of dexamethasone on renal tubular taurocholate transport, although these steroids have previously been shown to upregulate the ileal ASBT. Neither the clearance studies nor the uptake experiments of freshly isolated proximal tubular cells showed a significant difference after treatment of male rats (60µg/100 g body weight; p>0.05). Western blot analysis could not show a difference of ASBT-protein amount. Thus, we could exclude possible regulation of the ASBT in the proximal tubule.Aachen : Publikationsserver der RWTH Aachen University 100 S. : Ill., graph. Darst. (2007). = Aachen, Techn. Hochsch., Diss., 2007info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionPublikationsserver der RWTH Aachen University2007info:eu-repo/semantics/openAccessDEhttps://publications.rwth-aachen.de/record/52279https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-114515%22StudentsStudent Financial Aid ProvidersTeachersResearchersinfo:eu-repo/semantics/altIdentifier/urn/urn:nbn:de:hbz:82-opus-20071