Regulation of renal oatp mRNA expression by testosterone.

Abstract

A recently cloned cDNA encodes the so-called "organic anion-transporting polypeptide" (i.e., oatp), which is expressed in rat liver and in the kidney S3 proximal tubule. functional characterization of the cloned transporter indicates that estradiol 17 beta-D-glucuronide is a major substrate. Because the urinary excretion of glucuronidated steroids differs between males and females, we hypothesized that renal oatp expression may be under sex hormone control. Total RNA was isolated from male or female kidneys and probed with a digoxigenin-labeled oatp antisense riboprobe. Expression of oatp mRNA expression was quantitated by densitometry from Northern blots. Male kidneys expressed at least six distinct oatp transcripts (approximately 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 only the 3.2-kb band was consistently detectable. Administering testosterone to female rats increased, and administering estradiol (E2) to male rats decreased, the steady-state levels of renal oatp mRNA. Gonadectomized male and female rats, as well as adrenalectomized male rats, were given pharmacological hormone replacement (testosterone, E2, or dexamethasone, respectively) by subcutaneous osmotic minipump. Castration of male rats produced a dramatic drop in the steady-state level of all six renal oatp transcripts. These were returned to normal by testosterone replacement. In contrast, there was no regulation of hepatic oatp mRNA expression by testosterone. Renal oatp mRNA expression in female rats was mildly increased by oophorectomy. Administration of E2 to oophorectomized females moderately suppressed renal oatp mRNA expression. Adrenalectomy produced a small decrease in oatp expression, but dexamethasone replacement failed to return expression to normal. We conclude that renal oatp mRNA expression is under strong (stimulatory) testosterone 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.