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

Abstract

During water deprivation, prostaglandin E(2) (PGE(2)), formed by renal medullary interstitial cells (RMICs), feedback inhibits the actions of antidiuretic hormone. Interstitial PGE(2) concentrations represent the net of both PGE(2) synthesis by cyclooxygenase (COX) and PGE(2) uptake 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 [(3)H]PGE(2) to a level 5- to 10-fold above background and with a characteristic time-dependent "overshoot." Inhibitory constants (K(i)) 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 PGE(2) by 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, PGE(2) release 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 PGE(2) synthesis and PGT-mediated PGE(2) uptake in RMICs.

Diabetic microangiopathy: Pathogenetic insights and novel therapeutic approaches

“…TonEBP/NFAT5 is a master transcription factor of osmosensing genes responsive to hyperosmolar stress, including pro-inflammatory cytokines such as TNF-α in macrophages [84]. In renal medullary epithelial cells, hyperosmolar stress increases COX-2 promoter activity in a luciferase reporter assay [85,86]. In addition, hypertonic saline has been reported to induce COX-2 in rat macrophages [87] and human ECs [88].…”

COX-2 gene polymorphisms and protein expression in renomedullary interstitial cell tumors

“…In the kidney, inducible isoform of prostaglandin-endoperoxidase synthase 2 (prostaglandin G/H synthase and cyclooxygenase, PTGS2) commonly known as cyclooxygenase-2 (COX-2) is expressed in the macula densa and medullary interstitial cells where COX-2 is highly regulated in response to alterations in extracellular hyperosmolarity [6]. COX-2 metabolites have been implicated in mediation of renin release, regulation of sodium excretion, and maintenance of renal blood flow [7,8].…”

A Novel Transporter of SLC22 Family Specifically Transports Prostaglandins and Co-localizes with 15-Hydroxyprostaglandin Dehydrogenase in Renal Proximal Tubules

“…To limit or terminate PG actions on the target receptors, some mechanisms must exist for the clearance of PGs in the proximity of the sites of action in the kidney. In line with this notion, the aforementioned PG transporter PGT that is expressed mainly in interstitial cells in renal medulla has been suggested to affect tubular sodium and water reabsorption through regulating local PGE 2 concentrations in the renal medulla (6,7). However, there have been no reports on the renal cortex PG clearance.…”