Molecular Physiology of Renal p-Aminohippurate Secretion

Physiology ◽  
2001 ◽  
Vol 16 (3) ◽  
pp. 114-118 ◽  
Author(s):  
Gerhard Burckhardt ◽  
Andrew Bahn ◽  
Natascha A. Wolff
Keyword(s):  
Organic Anion ◽  
Organic Anions ◽  
Proximal Tubules ◽  
Organic Anion Transporter ◽  
Molecular Physiology ◽  
Renal Proximal Tubules ◽  
Anion Transporter ◽  
Tubule Lumen ◽  
Tubule Cells ◽  
Species Specific

Renal proximal tubules secrete various organic anions, including drugs and p-aminohippurate (PAH). Uptake of PAH from blood into tubule cells occurs by exchange with intracellular α-ketoglutarate and is mediated by the organic anion transporter 1. PAH exit into tubule lumen is species specific and may involve ATP-independent and -dependent transporters.

Acute regulation of OAT3-mediated estrone sulfate transport in isolated rabbit renal proximal tubules

2004 ◽  
Vol 287 (5) ◽  
pp. F1021-F1029 ◽  
Author(s):  
S. Soodvilai ◽  
V. Chatsudthipong ◽  
K. K. Evans ◽  
S. H. Wright ◽  
W. H. Dantzler
Keyword(s):  
Organic Anion ◽  
Basolateral Membrane ◽  
Anion Transport ◽  
Proximal Tubules ◽  
Organic Anion Transporter ◽  
Dependent Manner ◽  
Organic Anion Transport ◽  
Renal Proximal Tubules ◽  
Estrone Sulfate ◽  
Anion Transporter

We investigated the regulation of organic anion transport driven by the organic anion transporter 3 (OAT3), a multispecific OAT localized at the basolateral membrane of the renal proximal tubule. PMA, a PKC activator, inhibited uptake of estrone sulfate (ES), a prototypic substrate for OAT3, in a dose- and time-dependent manner. This inhibition was reduced by 100 nM bisindoylmaleimide I (BIM), a specific PKC inhibitor. The α1-adrenergic receptor agonist phenylephrine also inhibited ES uptake, and this effect was reduced by BIM. These results suggest that PKC activation downregulates OAT3-mediated organic anion transport. In contrast, epidermal growth factor (EGF) increased ES uptake following activation of MAPK. Exposure to PGE2 or dibutyryl (db)-cAMP also enhanced ES uptake. Stimulation produced by PGE2 and db-cAMP was prevented by the PKA inhibitor H-89, indicating that this stimulation required PKA activation. In addition, inhibition of cyclooxygenase 1 (COX1) (but not COX2) inhibited ES uptake. Furthermore, the stimulatory effect of EGF was eliminated by inhibition of either COX1 or PKA. These data suggest that EGF stimulates ES uptake by a process in which MAPK activation results in increased PGE2 production that, in turn, activates PKA and subsequently stimulates ES uptake. Interestingly, EGF did not induce upregulation immediately following phenylephrine-induced downregulation; and phenylephrine did not induce downregulation immediately after EGF-induced upregulation. These data are the first to show the regulatory response of organic anion transport driven by OAT3 in intact renal proximal tubules.

Molecular physiology of renal organic anion transporters

2006 ◽  
Vol 290 (2) ◽  
pp. F251-F261 ◽  
Author(s):  
Takashi Sekine ◽  
Hiroki Miyazaki ◽  
Hitoshi Endou
Keyword(s):  
Organic Anion ◽  
Organic Anions ◽  
Organic Anion Transporter ◽  
Transepithelial Transport ◽  
Gene Localization ◽  
Organic Anion Transporters ◽  
Molecular Physiology ◽  
Anion Transporters ◽  
Anion Transporter ◽  
Molecular Information

Recent advances in molecular biology have identified three organic anion transporter families: the organic anion transporter (OAT) family encoded by SLC22A, the organic anion transporting peptide (OATP) family encoded by SLC21A ( SLCO), and the multidrug resistance-associated protein (MRP) family encoded by ABCC. These families play critical roles in the transepithelial transport of organic anions in the kidneys as well as in other tissues such as the liver and brain. Among these families, the OAT family plays the central role in renal organic anion transport. Knowledge of these three families at the molecular level, such as substrate selectivity, tissue distribution, and gene localization, is rapidly increasing. In this review, we will give an overview of molecular information on renal organic anion transporters and describe recent topics such as the regulatory mechanisms and molecular physiology of urate transport. We will also discuss the physiological roles of each organic anion transporter in the light of the transepithelial transport of organic anions in the kidneys.

scholarly journals Organic anion transporter 3 (OAT3) and renal transport of the metal chelator 2,3-dimercapto-1-propanesulfonic acid (DMPS)

2010 ◽  
Vol 88 (2) ◽  
pp. 141-146 ◽  
Author(s):  
Matthias Rödiger ◽  
Xiaohong Zhang ◽  
Bernhard Ugele ◽  
Nikolaus Gersdorff ◽  
Stephen H. Wright ◽  
...  
Keyword(s):  
Organic Anion ◽  
Proximal Tubules ◽  
Organic Anion Transporter ◽  
Hek293 Cells ◽  
Renal Transport ◽  
Renal Proximal Tubules ◽  
Metal Chelator ◽  
Anion Transporter ◽  
Intact Rabbit ◽  
Organic Anion Transporter 3

Recent investigations involving intact rabbit renal proximal tubules indicated that organic anion transporter 3 (OAT3) may be involved in the transport of 2,3-dimercapto-1-propanesulfonic acid (DMPS). Therefore, we evaluated the interaction of OAT3 with DMPS to determine the effect of OAT3 on basolateral DMPS uptake. We used stably transfected HEK293 cells expressing human and rabbit orthologs of the exchanger OAT1 and OAT3. Using 6-carboxyfluorescein (6-CF) as a substrate, the IC50 determinations for reduced DMPS (DMPSH) revealed a stronger interaction with OAT1 than with OAT3 (rbOAT1, 123.3 ± 13.7; hOAT1, 85.1 ± 8.8; rbOAT3, 171.7 ± 22.3; and hOAT3, 172.2 ± 36.4 µmol/L). However, inhibition of 6-CF uptake by the oxidized form of DMPS (DMPSS), the main form of DMPS in the blood, showed a greater affinity for OAT3 (rbOAT1, 237.4 ± 23; hOAT1, 104.6 ± 13.1; rbOAT3, 52.4 ± 7.6; and hOAT3, 31.6 ± 6.6 µmol/L). To determine whether DMPSH and DMPSS are substrates for OAT3, we performed efflux studies with [14C]glutarate and inwardly directed gradients of glutarate. The inhibitors trans-stimulated the efflux of [14C]glutarate, suggesting that OAT3 may be able to transport both forms of DMPS. On the basis of the substantial interaction of OAT3 with DMPSS, we conclude that OAT3 represents the dominant basolateral player in renal detoxification processes resulting from use of DMPS.

scholarly journals Immunohistochemical Localization of Multispecific Renal Organic Anion Transporter 1 in Rat Kidney

1999 ◽  
Vol 10 (3) ◽  
pp. 464-471 ◽  
Author(s):  
AKIHIRO TOJO ◽  
TAKASHI SEKINE ◽  
NORIKO NAKAJIMA ◽  
MAKOTO HOSOYAMADA ◽  
YOSHIKATSU KANAI ◽  
...  
Keyword(s):  
Rat Kidney ◽  
Organic Anion ◽  
Basolateral Membrane ◽  
Organic Anions ◽  
Proximal Tubules ◽  
Organic Anion Transporter ◽  
Electron Microscopic ◽  
Renal Vasculature ◽  
Initial Portion ◽  
Anion Transporter

Abstract. Renal proximal convoluted tubules have an important role, i.e., to excrete organic anions, including numerous drugs and endogenous substances. Recently, multispecific organic anion transporter 1 (OAT1) was isolated from rat kidney. In this study, the cellular and subcellular localization of OAT1 in rat kidney was investigated. Kidneys from normal rats were perfused and fixed with periodate-lysine-paraformaldehyde solution and were then processed for immunohistochemical analysis using the labeled streptavidin-biotin method, preembedding horseradish peroxidase method, and immunogold method. Light microscopic examination revealed immunostaining for OAT1 in the middle portion of the proximal tubule (S2 segment), but not in the initial portion of the proximal convoluted tubule, next to the glomerulus. Nephron segments other than the S2 segment and the renal vasculature were not stained with antibody to OAT1. Electron-microscopic observation using a preembedding method revealed that OAT1 was exclusively expressed in the basolateral membrane of S2 segments of proximal tubules. The immunogold method showed no labeling for OAT1 in the cytoplasmic vesicles, suggesting that OAT1 may not move together with organic anions into the cells. These results are consistent with previous physiologic data showing that organic anions, including para-aminohippurate, are taken up by the basolateral Na+-independent organic anion/dicarboxylate exchanger and excreted at S2 segments. In conclusion, OAT1 was localized to the basolateral membrane of S2 segments of proximal tubules in rat kidneys.

Renal organic anion transporter 1 is maldistributed and diminishes in proximal tubule cells but increases in vasculature after ischemia and reperfusion

2008 ◽  
Vol 295 (6) ◽  
pp. F1807-F1816 ◽  
Author(s):  
Osun Kwon ◽  
Wei-Wei Wang ◽  
Shane Miller
Keyword(s):  
Proximal Tubule ◽  
Ischemia Reperfusion ◽  
Organic Anion ◽  
Basolateral Membrane ◽  
Kidney Injury ◽  
Organic Anion Transporter ◽  
Membrane Domain ◽  
Proximal Tubule Cells ◽  
Anion Transporter ◽  
Tubule Cells

Renal solute clearances are reduced in ischemic acute kidney injury. However, the mechanisms explaining how solute clearance is impaired have not been clarified. Recently, we reported that cadaveric renal allografts exhibit maldistribution of organic anion transporter 1 (OAT1) in proximal tubule cells after ischemia and reperfusion, resulting in impairment of PAH clearance. In the present study, we characterized renal OAT1 in detail after ischemia-reperfusion using a rat model. We analyzed renal OAT1 using confocal microscopy with a three-dimensional reconstruction of serial optical images, Western blot, and quantitative real-time RT-PCR. OAT1 was distributed to basolateral membranes of proximal tubule cells in controls. With ischemia, OAT1 decreased in basolateral membrane, especially in the lateral membrane domain, and appeared diffusely in cytoplasm. After reperfusion following 60-min ischemia, OAT1 often formed cytoplasmic aggregates. The staining for OAT1 started reappearing in lateral membrane domain 1 h after reperfusion. The basolateral membrane staining was relatively well discernable at 240 h of reperfusion. Of note, a distinct increase in OAT1 expression was noted in vasculature early after ischemia and after reperfusion. The total amount of OAT1 protein expression in the kidney diminished after ischemia-reperfusion in a duration-dependent manner until 72 h, when they began to recover. However, even at 240 h, the amount of OAT1 did not reach control levels. The kidney tissues tended to show a remarkable but transient increase in mRNA expression for OAT1 at 5 min of ischemia. Our findings may provide insights of renal OAT1 in its cellular localization and response during ischemic acute kidney injury and recovery from it.

scholarly journals Olfactory mucosa-expressed organic anion transporter, Oat6, manifests high affinity interactions with odorant organic anions

2006 ◽  
Vol 351 (4) ◽  
pp. 872-876 ◽  
Author(s):  
Gregory Kaler ◽  
David M. Truong ◽  
Derina E. Sweeney ◽  
Darren W. Logan ◽  
Megha Nagle ◽  
...  
Keyword(s):  
Organic Anion ◽  
Organic Anions ◽  
Olfactory Mucosa ◽  
Organic Anion Transporter ◽  
High Affinity ◽  
Anion Transporter

Transport of a fluorescent cAMP analog in teleost proximal tubules

2007 ◽  
Vol 293 (6) ◽  
pp. R2382-R2389 ◽  
Author(s):  
Valeska Reichel ◽  
Rosalinde Masereeuw ◽  
Jeroen J. M. W. van den Heuvel ◽  
David S. Miller ◽  
Gert Fricker
Keyword(s):  
Fundulus Heteroclitus ◽  
Organic Anion ◽  
Membrane Vesicles ◽  
Proximal Tubules ◽  
Organic Anion Transporter ◽  
Renal Tubules ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Camp Analog ◽  
Anion Transporter

Previous studies have shown that killifish ( Fundulus heteroclitus) renal proximal tubules express a luminal membrane transporter that is functionally and immunologically analogous to the mammalian multidrug resistance-associated protein isoform 2 (Mrp2, ABCC2). Here we used confocal microscopy to investigate in killifish tubules the transport of a fluorescent cAMP analog (fluo-cAMP), a putative substrate for Mrp2 and Mrp4 (ABCC4). Steady-state luminal accumulation of fluo-cAMP was concentrative, specific, and metabolism-dependent, but not reduced by high K+ medium or ouabain. Transport was not affected by p-aminohippurate (organic anion transporter inhibitor) or p-glycoprotein inhibitor (PSC833), but cell-to-lumen transport was reduced in a concentration-dependent manner by Mrp inhibitor MK571, leukotriene C4 (LTC4), azidothymidine (AZT), cAMP, and adefovir; the latter two compounds are Mrp4 substrates. Although MK571 and LTC4 reduced transport of the Mrp2 substrate fluorescein-methotrexate (FL-MTX), neither cAMP, adefovir, nor AZT affected FL-MTX transport. Fluo-cAMP transport was not reduced when tubules were exposed to endothelin-1, Na nitroprusside (an nitric oxide generator) or phorbol ester (PKC activator), all of which signal substantial reductions in cell-to-lumen FL-MTX transport. Fluo-cAMP transport was reduced by forskolin, and this reduction was blocked by the PKA inhibitor H-89. Finally, in membrane vesicles from Spodoptera frugiperda (Sf9) cells containing human MRP4, ATP-dependent and specific uptake of fluo-cAMP could be demonstrated. Thus, based on inhibitor specificity and regulatory signaling, cell-to-lumen transport of fluo-cAMP in killifish renal tubules is mediated by a transporter distinct from Mrp2, presumably a teleost form of Mrp4.

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