Downregulation of organic anion transporters OAT1 and OAT3 correlates with impaired secretion of para-aminohippurate after ischemic acute renal failure in rats

2007 ◽  
Vol 292 (5) ◽  
pp. F1599-F1605 ◽  
Author(s):  
R. Schneider ◽  
C. Sauvant ◽  
B. Betz ◽  
M. Otremba ◽  
D. Fischer ◽  
...  
Keyword(s):  
Renal Failure ◽  
Acute Renal Failure ◽  
Organic Anion ◽  
Organic Anions ◽  
Organic Anion Transporters ◽  
Protein Levels ◽  
Anion Transporters ◽  
Pah Clearance ◽  
Ischemic Acute Renal Failure

Ischemic acute renal failure (iARF) was described to reduce renal extraction of the organic anion para-aminohippurate (PAH) in humans. The rate-limiting step of renal organic anion secretion is its basolateral uptake into proximal tubular cells. This process is mediated by the organic anion transporters OAT1 and OAT3, which both have a broad spectrum of substrates including a variety of pharmaceutics and toxins. Using a rat model of iARF, we investigated whether impairing the secretion of the organic anion PAH might be associated with downregulation of OAT1 or OAT3. Inulin and PAH clearance was determined starting from 6 up to 336 h after ischemia-reperfusion (I/R) injury. Net secretion of PAH was calculated and OAT1 as well as OAT3 expression was analyzed by RT-PCR and Western blotting. Inulin and PAH clearance along with PAH net secretion were initially diminished after I/R injury with a gradual recovery during follow-up. This initial impairment after iARF was accompanied by decreased mRNA and protein levels of OAT1 and OAT3 in clamped animals compared with sham-operated controls. In correlation to the improvement of kidney function, both mRNA and protein levels of OAT1 and OAT3 were upregulated during the follow-up. Thus decreased expression of OAT1 and OAT3 is sufficient to explain the decline of PAH secretion after iARF. As a result, this may have substantial impact on excretion kinetics and half-life of organic anions. As a consequence, the biological effects of a variety of organic anions may be affected after iARF.

Erythropoietin alters the pharmacokinetics of organic anions mainly eliminated by the kidney in rats

2021 ◽  
Vol 99 (4) ◽  
pp. 368-377
Author(s):  
María Julia Severin ◽  
María Herminia Hazelhoff ◽  
Romina Paula Bulacio ◽  
María Eugenia Mamprin ◽  
Anabel Brandoni ◽  
...  
Keyword(s):  
Organic Anion ◽  
Elimination Rate ◽  
Renal Tissue ◽  
Organic Anions ◽  
Saline Control ◽  
Control Group ◽  
Anion Transporters ◽  
Male Wistar Rats ◽  
Pah Clearance ◽  
Renal Expression

Erythropoietin (EPO) is a cytokine originally used for its effects on the hematopoietic system, and is widely prescribed around the world. In the present study, the effects of EPO administration on p-aminohippurate (PAH, a prototype organic anion) pharmacokinetics and on the renal expression of PAH transporters were evaluated. Male Wistar rats were treated with EPO or saline (control group). After 42 h, PAH was administered, and plasma samples were obtained at different time points to determine PAH levels. PAH levels in renal tissue and urine were also assessed. The renal expression of PAH transporters was evaluated by Western blotting. EPO-treated rats showed an increase in PAH systemic clearance, in its elimination rate constant, and in urinary PAH levels, while PAH in renal tissue was decreased. Moreover, EPO administration increased the expression of the transporters of the organic anions evaluated. The EPO-induced increase in PAH clearance is accounted for by the increase in its renal secretion mediated by the organic anion transporters. The goal of this study is to add important information to the wide knowledge gap that exists regarding drug–drug interactions. Owing to the global use of EPO, these results are useful in terms of translation into clinical practice.

scholarly journals Downregulation of organic anion transporters in rat kidney under ischemia/reperfusion-induced qacute renal failure

2007 ◽  
Vol 71 (6) ◽  
pp. 539-547 ◽  
Author(s):  
T. Matsuzaki ◽  
H. Watanabe ◽  
K. Yoshitome ◽  
T. Morisaki ◽  
A. Hamada ◽  
...  
Keyword(s):  
Renal Failure ◽  
Rat Kidney ◽  
Ischemia Reperfusion ◽  
Organic Anion ◽  
Organic Anion Transporters ◽  
Anion Transporters

Mg2+-Malate Co-Transport, a Mechanism for Na+-Independent Mg2+ Transport in Neurons of the Leech Hirudo medicinalis

2005 ◽  
Vol 94 (1) ◽  
pp. 441-453 ◽  
Author(s):  
Dorothee Günzel ◽  
Karin Hintz ◽  
Simone Durry ◽  
Wolf-Rüdiger Schlue
Keyword(s):  
Organic Anion ◽  
Inhibitory Effect ◽  
Organic Anions ◽  
Hirudo Medicinalis ◽  
Disulfonic Acid ◽  
Organic Anion Transporters ◽  
Experimental Conditions ◽  
Physiological Conditions ◽  
Anion Transporters ◽  
Proposed Model

Mg2+-extrusion from Mg2+-loaded neurons of the leech, Hirudo medicinalis, is mediated mainly by Na+/Mg2+ antiport. However, in a number of leech neurons, Mg2+ is extruded in the nominal absence of extracellular Na+, indicating the existence of an additional, Na+-independent Mg2+ transport mechanism. This mechanism was investigated using electrophysiological and microfluorimetrical techniques. The rate of Na+-independent Mg2+ extrusion from Mg2+-loaded leech neurons was found to be independent of extracellular Ca2+, K+, NO3−, HCO3−, SO42−, HPO42−, and of intra- and extracellular pH. Na+-independent Mg2+ extrusion was not inhibited by 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS), furosemide, ouabain, vanadate, iodoacetate, 4-amino-hippurate, or α-cyano-4-hydroxycinnamate and was not influenced by changes in the membrane potential in voltage-clamp experiments. Na+-independent Mg2+ extrusion was, however, inhibited by the application of 2 mM probenecid, a blocker of organic anion transporters, suggesting that Mg2+ might be co-transported with organic anions. Extracellularly, of all organic anions tested (malate, citrate, lactate, α-ketoglutarate, and 4-amino-hippurate) only high, but physiological, concentrations of malate (30 mM) had a significant inhibitory effect on Na+-independent Mg2+ extrusion. Intracellularly, iontophoretically injected malate, citrate, or fura-2, but not Cl−, α-ketoglutarate, glutamate, succinate, or urate, were stimulating Na+-independent Mg2+ extrusion from those neurons that initially did not extrude Mg2+ in Na+-free solutions. Our data indicate that Mg2+ is co-transported with organic anions, preferably with malate, the predominant extracellular anion in the leech. The proposed model implies that, under experimental conditions, malate drives Mg2+ extrusion, whereas under physiological conditions, malate is actively taken up, driven by Mg2+, so that malate can be metabolized.

scholarly journals Arsenic and Mercury Containing Traditional Chinese Medicine (Realgar and Cinnabar) Strongly Inhibit Organic Anion Transporters, Oat1 and Oat3,In Vivoin Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Wen-Hao Yu ◽  
Na Zhang ◽  
Jin-Feng Qi ◽  
Chen Sun ◽  
Yong-Hui Wang ◽  
...  
Keyword(s):  
Heavy Metals ◽  
Renal Failure ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Organic Anion ◽  
Pharmacokinetic Parameters ◽  
Organic Anion Transporters ◽  
Toxic Heavy Metals ◽  
Anion Transporters

Toxic heavy metals, including mercury (Hg) and arsenic (As), accumulate preferentially in kidneys and always cause acute renal failure. The aim of this study was to investigate whether these samples affect organic anion transporters, Oat1 and Oat3,in vivoin mice kidney. Mice (n=10) were orally treated with investigational samples. After last administration, all mice were i.v.p-aminohippuric acid (PAH), and the blood and kidneys samples were collected. The concentrations of PAH were quantified by spectrophotometry. mRNA expressions of Oat1 and Oat3 were assayed by real-time PCR. In comparison with corresponding control, major pharmacokinetic parameters of PAH in sera were significantly changed by investigational samples (p<0.05), PAH accumulations in the kidney tissues were significantly higher (p<0.05), PAH uptake by renal slices was greatly reduced, Oat1 and Oat3 mRNA expression were significantly inhibited in investigational sample groups. Arsenic and mercury containing traditional Chinese medicine (Realgar and Cinnabar) probably induce kidney damage through inhibiting several members of the organic anion transporters (such as OAT1 and OAT3).

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 Macrophages possess probenecid-inhibitable organic anion transporters that remove fluorescent dyes from the cytoplasmic matrix.

1987 ◽  
Vol 105 (6) ◽  
pp. 2695-2702 ◽  
Author(s):  
T H Steinberg ◽  
A S Newman ◽  
J A Swanson ◽  
S C Silverstein
Keyword(s):  
Fluorescent Dyes ◽  
Lucifer Yellow ◽  
Organic Anion ◽  
Peritoneal Macrophages ◽  
Organic Anions ◽  
Organic Anion Transporters ◽  
Extracellular Medium ◽  
Cytoplasmic Matrix ◽  
Anion Transporters ◽  
Cytoplasmic Vacuoles

We introduced several membrane-impermeant fluorescent dyes, including Lucifer Yellow, carboxyfluorescein, and fura-2, into the cytoplasmic matrix of J774 cells and thioglycollate-elicited mouse peritoneal macrophages by ATP permeabilization of the plasma membrane and observed the subsequent fate of these dyes. The dyes did not remain within the cytoplasmic matrix; instead they were sequestered within phase-lucent cytoplasmic vacuoles and released into the extracellular medium. We used Lucifer Yellow to study these processes further. In cells incubated at 37 degrees C, 87% of Lucifer Yellow was released from the cells within 30 min after dye loading. The dye that remained within the cells at this time was predominantly within cytoplasmic vacuoles. Lucifer yellow transport was temperature dependent and occurred against a concentration gradient; therefore it appeared to be an energy-requiring process. The fluorescent dyes used in these studies are all organic anions. We therefore examined the ability of probenecid (p-[dipropylsulfamoyl]benzoic acid), which blocks organic anion transport across many epithelia, to inhibit efflux of Lucifer Yellow, and found that this drug inhibited this process in a dose-dependent and reversible manner. Efflux of Lucifer Yellow from the cells did not require Na+ co-transport or Cl- antiport; however, it was inhibited by lowering of the extracellular pH. These experiments indicate that macrophages possess probenecid-inhibitable transporters which are similar in their functional properties to organic anion transporters of epithelial cells. Such organic anion transporters have not been described previously in macrophages; they may mediate the release of naturally occurring organic anions such as prostaglandins, leukotrienes, glutathione, bilirubin, or lactate from macrophages.

scholarly journals Immunolocalization of Multispecific Organic Anion Transporters, OAT1, OAT2, and OAT3, in Rat Kidney

2002 ◽  
Vol 13 (4) ◽  
pp. 848-857 ◽  
Author(s):  
Ryoji Kojima ◽  
Takashi Sekine ◽  
Masanao Kawachi ◽  
Seok Ho Cha ◽  
Yoshio Suzuki ◽  
...  
Keyword(s):  
Rat Kidney ◽  
Organic Anion ◽  
Basolateral Membrane ◽  
Organic Anions ◽  
Proximal Tubules ◽  
Transepithelial Transport ◽  
Thick Ascending Limb ◽  
Apical Surface ◽  
Organic Anion Transporters ◽  
Anion Transporters

ABSTRACT. Recently, a family of multispecific organic anion transporters has been identified, and several isoforms have been reported. However, the physiologic and pharmacologic roles of each isoform, except OAT1, in the transepithelial transport of organic anions in the kidney remain to be elucidated. To address this issue, it is essential to determine the intrarenal distribution and membrane localization of each OAT isoform along the nephron. In this study, the intrarenal distributions of rOAT1, rOAT2, and rOAT3 were investigated by an immunofluorescence method that used frozen rat serial kidney sections. Confocal microscopic analysis showed that immunoreactivity for rOAT1 was detected exclusively in the proximal tubules (S1, S2, S3) in the cortex with basolateral membrane staining. rOAT2 was detected in the apical surface of the tubules in the medullary thick ascending limb of Henle’s loop (MTAL) and cortical and medullary collecting ducts (CD). rOAT3 was localized in the basolateral digitation of the cell membrane in all the segments (S1, S2, and S3) of the proximal tubules, MTAL, cortical TAL, connecting tubules, and cortical and medullary CD. These results on the distribution of each OAT isoform will facilitate the understanding of the role of OATs in the renal processing of organic anions.

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