Tubular mechanisms determining the urinary excretion of tritiated prostaglandin E2 in the anaesthetized rat.

Haylor, J.; Lote, Christopher J.; Towers, Jeffrey D.

doi:10.1113/jphysiol.1988.sp017234

Cited by 6 publications

(3 citation statements)

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“…If a four-fold increase also would be the case in fever in humans, PGE 2 concentrations possibly could reach some tens of nanomolar that is in the range of PGE 2 action on OAT in this study. Protein binding of PGE 2 in plasma is approximately 60% (22). Therefore, protein binding does not change the free concentration of PGE 2 by orders of magnitude but only by half.…”

Section: Discussionmentioning

confidence: 96%

“…However, it is known that prostaglandins (and their respective metabolites) are excreted to a major extent by the kidneys, and blood levels are highly dependent on renal prostaglandin excretion (21). Because of protein binding, proximal tubular secretion of PGE 2 plays a major role in renal excretion (22). Because PGE 2 is a substrate for both OAT1 and OAT3 (14), these transporters represent the rate-limiting basolateral uptake step of proximal tubule PGE 2 secretion.…”

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confidence: 99%

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Prostaglandin E2 Inhibits Its Own Renal Transport by Downregulation of Organic Anion Transporters rOAT1 and rOAT3

Sauvant¹,

Holzinger²,

Gekle³

2006

Journal of the American Society of Nephrology

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Prostaglandin E 2 (PGE 2 ) is the principal mediator of fever and inflammation. Recently, evidence emerged that during febrile response, PGE 2 that is generated in the periphery enters the hypothalamus and contributes to the maintenance of fever. In a rat model of fever generation, peripheral PGE 2 is increased, whereas clearance by metabolism of peripheral PGE 2 is downregulated. The major route of PGE 2 excretion is via the renal proximal tubular organic anion secretory system, where basolateral uptake that is mediated by renal organic anion transporter 1 (rOAT1) and rOAT3 is rate limiting. Therefore, it was hypothesized that PGE 2 itself will abolish its excretion by rOAT1 or rOAT3. Fluorescein was used as a prototypic organic anion, and NRK-52E cells from rat served as a proximal tubular model system. PGE 2 time-dependently downregulates basolateral organic anion uptake, without affecting cell volume or cell protein, recirculation of counter ions, or proximal tubular transport systems in general. In addition, PGE 2 diminishes expression of both rOAT1 and rOAT3. Both organic anion uptake and expression of rOAT1 and rOAT3 are dose-dependently downregulated by PGE 2 . These findings suggest that during fever or inflammation, renal secretory transport of PGE 2 is reduced, contributing to elevated PGE 2 levels in blood. These data fit into the hypothetical concept of peripheral PGE 2 's playing a significant role in fever. The described regulatory mechanism may also be of relevance in chronic inflammatory events. Moreover, the data presented could explain why increased plasma urate levels occur in diseases that go along with increased levels of PGE 2 .J Am Soc Nephrol 17: 46 -53, 200646 -53, . doi: 10.1681 T he organic anion transport system of the renal proximal tubule plays a crucial role in the excretion of a variety of potentially toxic compounds. This system consists of organic anion exchangers that are located at the basolateral membrane and a less well-characterized transport step at the apical membrane. The classical basolateral organic anion exchanger is the terminal step in a tertiary active transport system, dependent on an inward-directed Na ϩ gradient to drive the uptake of ␣-ketoglutarate, which then is exchanged for organic anions. It has been shown that OAT1 represents characteristics of the basolateral, polyspecific transporter for organic anions, which had been functionally described for some time (1). Recently, new evidence has indicated that organic anion transporter 3 (OAT3) (2), which also is located in the basolateral renal proximal tubular membrane, also works as an appropriate exchanger for organic anions and dicarboxylates (3,4). Moreover, additional homologues have been cloned and were called OAT2 (5), OAT4 (6), OAT5 (7), and OAT6 (8). These clones show 40 to 60% homology in amino acid sequence compared with OAT1 or OAT3, and they differ in substrate specificity and expression pattern. Furthermore, these latter proteins are not anion exchangers like OAT1 or OAT3 but seem to work as fac...

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

Prostaglandin E2 Inhibits Its Own Renal Transport by Downregulation of Organic Anion Transporters rOAT1 and rOAT3

Sauvant¹,

Holzinger²,

Gekle³

2006

Journal of the American Society of Nephrology

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“…1). (Of note, probenecid had previously been shown by other investigators to cause an acute decrease in blood pressure [25]). Overall, the findings are consistent with the hypothesis that inhibition of Oat3 via administration of sufficiently potent inhibitors could result in reduction of blood pressure.…”

Section: Blood Pressure Effects Of Oat3 Inhibitorsmentioning

confidence: 99%

Organic anion transporter 3 inhibitors as potential novel antihypertensives☆

Eraly

2008

Pharmacological Research

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Hypertension is an exceedingly common disease with potentially devastating complications. Unfortunately, existing treatments are often only partially effective, indicating the utility of the development of novel therapeutics. It has recently been discovered that loss of renal organic anion transporter 3 (Oat3) results in decreased blood pressure. This suggests (regardless of the underlying mechanisms, which are, as yet, unclear) that inhibition of Oat3 function might also decrease blood pressure, and, therefore, that inhibitors of Oat3 might serve as novel drugs in the treatment of hypertension. In support of this hypothesis, it has been found that at least some potent Oat3 inhibitors can lower blood pressure. These recent findings are discussed in the context of the alternating access model that has been proposed for organic anion transporter function, with particular attention to the little-appreciated phenomenon of trans-inhibition. Keywordshypertension; blood pressure; antihypertensive; organic anion transporter; Oat3; Oat3 inhibitor; alternating access; trans-inhibition Organic Anion Transport and Regulation of Blood PressureThe proximal tubule of the kidney mediates the efficient secretion of a diverse array of organic anionic compounds. The rate-limiting step in this secretion is the uptake of substrates from plasma into tubular cells across their basolateral membranes. This step operates via anion exchange, whereby intracellular dicarboxylates (particularly the Krebs cycle intermediate, α-ketoglutarate) are exchanged for extracellular (plasma) substrates (reviewed in [1,2]). Biochemical as well as knockout studies indicate that organic anion transporters 1 and 3 (Oat1 and Oat3) appear to underlie the basolateral uptake step of this pathway (reviewed in [3,4]). A large number of clinically important drugs are substrates of Oat1 and Oat3, including β-lactam antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), loop and thiazide diuretics, and antivirals, among others. Several organic anions of endogenous origin, including prostanoids, cyclic nucleotides, and various metabolites (e.g., short-chain fatty acids, Krebs cycle intermediates) are known to be substrates as well; however, in general, the physiological functions of the OATs are not as well-understood as their pharmacological roles [5].Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Among the multitude of factors that contribute to the regulation of blood pressure, perhaps the most important, at least with respect to renally mediated mechanisms, are the activity of the renin-angiotensin-aldoster...

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Contraluminal p-aminohippurate transport in the proximal tubule of the rat kidney

et al. 1991

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Using the stop-flow peritubular capillary microperfusion method the inhibitory potency (apparent Ki values) of cyclic nucleotides and prostanoids against contraluminal p-aminohippurate (PAH), dicarboxylate and sulphate transport was evaluated. Conversely the contraluminal transport rate of labelled cAMP, cGMP, prostaglandin E2, and prostaglandin D2 was measured and the inhibition by different substrates was tested. Cyclic AMP and its 8-bromo and dibutyryl analogues inhibited contraluminal PAH transport with an app. Ki,PAH of 3.4, 0.63 and 0.52 mmol/l. The respective app. Ki,PAH values of cGMP and its analogues are with 0.27, 0.04 and 0.05 mmol/l, considerably lower. None of the cyclic nucleotides tested interacted with contraluminal dicarboxylate, sulphate and N1-methylnicotinamide transport. ATP, ADP, AMP, adenosine and adenine as well as GTP, GDP, GMP, guanosine and guanine did not inhibit PAH transport while most of the phosphodiesterase inhibitors tested did. Time-dependent contraluminal uptake of [3H]cAMP and [3H]cGMP was measured at different starting concentrations and showed facilitated diffusion kinetics with the following parameters for cAMP: Km = 1.5 mmol/l, Jmax = 0.34 pmol S-1 cm-1, r (extracellular/intracellular amount at steady state) = 0.91; for cGMP: Km = 0.29 mmol/l, Jmax = 0.31 pmol S-1 cm-1, r = 0.55. Comparison of app. Ki,cGMP with app. Ki,PAH of ten substrates gave a linear relation with a ratio of 1.83 +/- 0.5. All prostanoids applied inhibited the contraluminal PAH transport; the prostaglandins E1, F1 alpha, A1, B1, E2, F2 alpha, D2, A2 and B2 with an app. Ki,PAH between 0.08 and 0.18 mmol/l. The app. Ki of the prostacyclins 6,15-diketo-13,14-dihydroxy-F1 alpha (0.22 mmol/l) and Iloprost (0.17 mmol/l) as well as that of leukotrienes B4 (0.2 mmol/l) was in the same range, while the app. Ki,PAH of the prostacyclins PGI2 (0.55 mmol/l), 6-keto-PGF1 alpha (0.77 mmol/l) and 2,3-dinor-6-keto-PGF1 alpha (0.57 mmol/l) as well as that of thromboxane B2 (0.36 mmol/l) was somewhat higher. None of these prostanoids inhibited contraluminal dicarboxylate transport and only PGB1, E2 and D2 inhibited contraluminal sulphate transport (app. Ki,SO4(2-) 5.4, 11.0, 17.9 mmol/l respectively). Contraluminal influx of labelled PGE2 showed complex transport kinetics with a mixed Km = 0.61 mmol/l and Jmax of 4.26 pmol S-1 cm-1. It was inhibited by probenecid, sulphate and indomethacin. Contraluminal influx of PGD2, however, was only inhibited by probenecid. The data indicate that cyclic nucleotides as well as prostanoids are transported by the contraluminal PAH transporter. For prostaglandin E2 a significant uptake through the sulphate transporter occurs in addition.(ABSTRACT TRUNCATED AT 400 WORDS)

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Tubular mechanisms determining the urinary excretion of tritiated prostaglandin E2 in the anaesthetized rat.

Abstract: SUMMARY The renal excretion of arterially injected tritiated prostaglandin E2 ([3H]PGE2)and its metabolites has been examined in the anaesthetized rat before and after the administration of probenecid (an inhibitor of proximal organic acid secretion

Cited by 6 publications

References 21 publications

Prostaglandin E2 Inhibits Its Own Renal Transport by Downregulation of Organic Anion Transporters rOAT1 and rOAT3

Prostaglandin E2 Inhibits Its Own Renal Transport by Downregulation of Organic Anion Transporters rOAT1 and rOAT3

Organic anion transporter 3 inhibitors as potential novel antihypertensives☆

Contraluminal p-aminohippurate transport in the proximal tubule of the rat kidney

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