REGULATION OF RENAL OATP MESSENGER-RNA EXPRESSION BY TESTOSTERONE

A recently cloned cDNA encodes the so-called ''organic anion-transport ing polypeptide'' (i.e., oatp), which is expressed in rat liver and in the kidney S3 proximal tubule. Functional characterization of the clo ned transporter indicates that estradiol 17 beta-D-glucuronide is a ma jor substrate. Because the urinary excretion of glucuronidated steroid s differs between males and females, we hypothesized that renal oatp e xpression may be under sex hormone control. Total RNA was isolated fro m male or female kidneys and probed with a digoxigenin-labeled oatp an tisense riboprobe. Expression of oatp mRNA expression was quantitated by densitometry from Northern blots. Male kidneys expressed at least s ix distinct oatp transcripts (similar to 4.0, 3.2, 2.9, 2.6, 1.7, and 1.2 kb). Of these, the 3.2-kb band was consistently the strongest. In female rats, renal oatp mRNA expression was markedly less, such that o nly the 3.2-kb band was consistently detectable. Administering testost erone to female rats increased, and administering estradiol (E2) to ma le rats decreased, the steady-state levels of renal oatp mRNA. Gonadec tomized male and female rats, as well as adrenalectomized male rats, w ere given pharmacological hormone replacement (testosterone, E2, or de xamethasone, respectively) by subcutaneous osmotic minipump. Castratio n of male rats produced a dramatic drop in the steady-state level of a ll six renal oatp transcripts. These were returned to normal by testos terone replacement. In contrast, there was no regulation of hepatic oa tp mRNA expression by testosterone. Renal oatp mRNA expression in fema le rats was mildly increased by oophorectomy. Administration of E2 to oophorectomized females moderately suppressed renal oatp mRNA expressi on. Adrenalectomy produced a small decrease in oatp expression, but de xamethasone replacement failed to return expression to normal. We conc lude that renal oatp mRNA expression is under strong (stimulatory) tes tosterone control and perhaps weaker (inhibitory) estrogen control. We speculate that this regulation of renal oatp expression is important in modulating the renal tubular secretion of conjugated E2.