Coordinate control of prostaglandin E2synthesis and uptake by hyperosmolarity in renal medullary interstitial cells

Abstract

During water deprivation, prostaglandin E2(PGE2), formed by renal medullary interstitial cells (RMICs), feedback inhibits the actions of antidiuretic hormone. Interstitial PGE2concentrations represent the net of both PGE2synthesis by cyclooxygenase (COX) and PGE2uptake by carriers such as PGT. We used cultured RMICs to examine the effects of hyperosmolarity on both PG synthesis and PG uptake in the same RMIC. RMICs expressed endogenous PGT as assessed by mRNA and immunoblotting. RMICs rapidly took up [3H]PGE2to a level 5- to 10-fold above background and with a characteristic time-dependent “overshoot.” Inhibitory constants ( Ki) for various PGs and PGT inhibitors were similar between RMICs and the cloned rat PGT. Increasing extracellular hyperosmolarity to the range of 335–485 mosM increased the net release of PGE2by RMICs, an effect that was concentration dependent, maximal by 24 h, reversible, and associated with increased expression of COX-2. Over the same time period, there was decreased cell-surface activity of PGT due to internalization of the transporter. With continued exposure to hyperosmolarity over 7–10 days, PGE2release remained elevated, COX-2 returned to baseline, and PGT-mediated uptake became markedly reduced. Our findings suggest that hyperosmolarity induces coordinated changes in COX-2-mediated PGE2synthesis and PGT-mediated PGE2uptake in RMICs.