Prostaglandin Signaling in the Renal Collecting Duct

Abstract

Prostaglandins mediate autacrine and paracrine signaling over short distances. We used the renal collecting duct as a model system to test the hypothesis that local control of prostaglandin signaling is achieved by expressing inactivation in the same cell as synthesis. Immunocytochemical studies demonstrated that renal collecting ducts in situ express the prostaglandin (PG) synthesis enzyme, cyclooxygenase-1 (COX-1), as well as both components of prostaglandin metabolic inactivation, i.e. the prostaglandin uptake carrier prostaglandin transporter (PGT) and the enzyme 15-hydroxyprostaglandin dehydrogenase. We characterized this system further using the collecting duct cell line Madin-Darby canine kidney (MDCK), which retains COX-2 and prostaglandin dehydrogenase expression but which has lost PGT expression. When we reintroduced PGT, it was correctly sorted to the apical membrane where it altered the sidedness of prostaglandin E2 (PGE2) release, a process we call "vectorial release via sided reuptake." Importantly, although COX-2 and prostaglandin dehydrogenase are expressed in the same MDCK cell, they must be compartmentalized because even in the presence of excess dehydrogenase newly synthesized PGE2 is released largely un-oxidized. However, when PGE2 undergoes first release and then PGT-mediated reuptake, significant oxidation takes place, suggesting that PGT imports PGE2 into the prostaglandin dehydrogenase compartment. Our data are consistent with a new model that offers significant new mechanisms for the fine control of eicosanoid signaling.Prostaglandins (PGs) 1 represent an extreme example of context-dependent autacrine or paracrine signaling. A single type of prostaglandin, PGE2, can activate any of four receptor subtypes (EP 1 , EP 2 , EP 3 , and EP 4 ) so as to mediate changes in physiological function as diverse as gastric acid secretion, body temperature, intraocular pressure, blood pressure, and airway reactivity (1-3).Even within a single organ, such as the kidney, PGE2 has diverse effects including afferent arteriolar vasodilatation, reduction of NaCl resorption by the thick ascending limb of Henle, vasodilatation of medullary vasa rectae, and inhibition of osmotic water flow in the cortical collecting duct (2). On a smaller scale, the renal collecting expresses luminal EP 4 receptors, activation of which increases Na ϩ reabsorption and increases water reabsorption, and basolateral EP 1 receptors, activation of which signals the opposite effects (4, 5). Clearly, to achieve the requisite fidelity in PGE2 signaling, rapid inactivation must occur.PG inactivation involves active uptake into the cell followed by cytoplasmic oxidation (6). Our laboratory identified the prostaglandin transporter PGT (Slc21a2; oatp2A1) (7), which is the lead candidate for the uptake step. Targeted deletion of mouse PGT results in death at post-natal day 1, most likely the result of an inability to inactivate circulating PGE2. 2 The enzyme 15-hydroxyprostaglandin dehydrogenase (PGDH) has been extensively characterized by ot...

Prostaglandin E2 modifies SMAD2 and promotes SMAD2–SMAD4 complex formation

“…Recently, specific prostaglandin transporter PGT has been cloned [16]. It has been thought that PGT takes up and oxidizes PGE 2 to the inactive metabolites, thus terminating PGE 2 actions [25]. However, our findings imply that PGE 2 take-up by PGT is the first step in novel intracellular function of PGE 2 .…”

Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury

“…The key event in preserving epithelial proliferation appears to be the achievement of high levels of PGE 2 in the pericryptal niche. PGE 2 has a short half-life and acts over short distances (34,35). Therefore, PSCs positioned closer to crypt epithelial cells should increase the local concentration of PGE 2 .…”

Interplay between the prostaglandin transporter OATP2A1 and prostaglandin E2-mediated cellular effects

“…This fact was supported by a study showing its coordinate expression together with enzymes of prostaglandin synthesis (e.g. COX-1) and degradation (15-hydroxy prostaglandin dehydrogenase) in the same cells of the rat cortical collecting duct [8]. For the human gastric mucosa different studies showed the localization of COX-1 and COX-2 in parietal cells and gastric glands of human stomach under normal and certain pathological conditions [28,29].…”

“…by the expression of several prostanoid receptors (EP1-EP4). For example, rat Oatp2a1 is expressed in cells of cortical collecting duct of rat kidney [8], and human OATP2A1 is localized e.g. in the neck region and deep pyloric glands of antrum and in parietal cells of gastric corpus [3].…”

“…Regarding the physiological and/or pathophysiological role of the prostaglandin transporter, it was postulated that OATP2A1 is responsible for the termination of the cellular effects of its substrates such as PGE 2 [4]. For example, in vitro studies indicate that the prostaglandin transporter is localized in a compartmental manner together with PGE 2 -metabolizing enzymes such as 15-hydroxy prostaglandin dehydrogenase and therefore contributes to the termination of prostaglandin effects [8,9].…”