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).

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.

Developmental expression of renal organic anion transporters in rat kidney and its effect on renal secretion of phenolsulfonphthalein

2012 ◽  
Vol 302 (12) ◽  
pp. F1640-F1649 ◽  
Author(s):  
Maki Nomura ◽  
Hideyuki Motohashi ◽  
Hiroko Sekine ◽  
Toshiya Katsura ◽  
Ken-ichi Inui
Keyword(s):  
Protein Expression ◽  
Organic Anion ◽  
Immunohistochemical Analysis ◽  
Tubular Secretion ◽  
Organic Anion Transporters ◽  
Adult Rats ◽  
Anion Transporters ◽  
Anionic Drugs ◽  
Clearance Study

Organic anion transporters (OAT1 and OAT3) and multidrug resistance-associated proteins (MRP2 and MRP4) play important roles in anionic drug secretion in renal proximal tubules. Changes in the expression of such transporters are considered to affect the tubular secretion of anionic drugs. The purpose of this study was to elucidate the developmental changes in the expression of OAT1, OAT3, MRP2, and MRP4 and their effects on the tubular secretion of drugs. The mRNA level of each transporter was measured by real-time PCR, and the protein expression was evaluated by Western blotting and immunohistochemical analysis. In addition, the tubular secretion of phenolsulfonphthalein (PSP) in infant (postnatal day 14) and adult rats was estimated based on in vivo clearance study. The protein expression of organic anion transporters were very low at postnatal day 0 and gradually increased with age. In postnatal day 14 rats, the expression of OAT1 and OAT3 seemed to be at almost mature levels, while MRP2 and MRP4 seemed to be at immature levels. Immunohistochemical analysis in the kidney of postnatal day 0 rats revealed OATs on the basolateral membrane and MRPs on the brush-border membrane. At postnatal day 0, the distribution of these transporters was restricted to the inner cortical region, while after postnatal day 14, it was identical to that in adult kidney. An in vivo clearance study revealed that the tubular secretion of PSP was significantly lower in postnatal day 14 rats than adult rats. These results indicate that age-dependent changes in organic anion transporter expression affect the tubular secretion of anionic drugs in pediatric patients.

Potent Inhibitors of Organic Anion Transporters 1 and 3 From Natural Compounds and Their Protective Effect on Aristolochic Acid Nephropathy

2020 ◽  
Vol 175 (2) ◽  
pp. 279-291
Author(s):  
Caiyu Li ◽  
Xue Wang ◽  
Yajuan Bi ◽  
Heshui Yu ◽  
Jing Wei ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Natural Compound ◽  
Aristolochic Acid ◽  
Organic Anion ◽  
Critical Role ◽  
Natural Compounds ◽  
Organic Anion Transporters ◽  
Herbal Products ◽  
Anion Transporters

Abstract Organic anion transporters 1 and 3 (OAT1 and OAT3) play a critical role in renal drug-drug interactions and are involved in the nephrotoxicity of many anionic xenobiotics. To date, relatively little is known about the interaction of natural compounds with OAT1 and OAT3. Of the 270 natural compounds screened in the present study, 21 compounds inhibited OAT1 and 45 compounds inhibited OAT3. Further concentration-dependent studies identified 7 OAT1 inhibitors and 10 OAT3 inhibitors with IC50 values of &lt;10 μM, and most of them were flavonoids, the most commonly ingested polyphenolic compounds in the diet and herbal products. Computational modeling of OAT1 and OAT3 revealed the important residues for the recognition of inhibitors. The two strong OAT inhibitors, namely wedelolactone and wogonin, were evaluated for their in vivo interactions with the OAT substrate aristolochic acid I (AAI), a natural compound causing aristolochic acid-induced nephropathy (AAN) in many species. The cytotoxicity of AAI increased in two OAT-overexpressing cell lines, with more cytotoxicity in OAT1-overexpressing cells, suggesting a more important role of OAT1 than OAT3 in AAN. Both wedelolactone and wogonin markedly increased serum AAI concentrations in AAI-treated rats and ameliorated kidney injuries in AAI-treated mice. To conclude, the present findings are of significant value in understanding natural compound-drug interactions and provide a natural source for developing treatments for AAN.

Transport of cimetidine by flounder and human renal organic anion transporter 1

2003 ◽  
Vol 284 (3) ◽  
pp. F503-F509 ◽  
Author(s):  
Birgitta C. Burckhardt ◽  
Stefan Brai ◽  
Sönke Wallis ◽  
Wolfgang Krick ◽  
Natascha A. Wolff ◽  
...  
Keyword(s):  
Organic Anion ◽  
Human Kidney ◽  
Organic Anion Transporter ◽  
In Vivo Studies ◽  
Xenopus Laevis Oocytes ◽  
Organic Anion Transporters ◽  
Anion Transporters ◽  
Anion Transporter ◽  
Inward Currents

The H2-receptor antagonist cimetidine is efficiently excreted by the kidneys. In vivo studies indicated an interaction of cimetidine not only with transporters for basolateral uptake of organic cations but also with those involved in excretion of organic anions. We therefore tested cimetidine as a possible substrate of the organic anion transporters cloned from winter flounder (fROAT) and from human kidney (hOAT1). Uptake of [3H]cimetidine into fROAT-expressing Xenopus laevis oocytes exceeded uptake into control oocytes. At −60-mV clamp potential, 1 mM cimetidine induced an inward current, which was smaller than that elicited by 0.1 mM PAH. Cimetidine concentrations exceeding 0.1 mM decreased PAH-induced inward currents, indicating interaction with the same transporter. At pH 6.6, no current was seen with 0.1 mM cimetidine, whereas at pH 8.6 a current was readily detectable, suggesting preferential translocation of uncharged cimetidine by fROAT. Oocytes expressing hOAT1 also showed [3H]cimetidine uptake. These data reveal cimetidine as a substrate for fROAT/hOAT1 and suggest that organic anion transporters contribute to cimetidine excretion in proximal tubules.

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

scholarly journals Optimal Methods of Antigen Retrieval for Organic Anion Transporters in Cryosections of the Rat Kidney

2009 ◽  
Vol 60 (1) ◽  
pp. 7-17 ◽  
Author(s):  
Hrvoje Brzica ◽  
Davorka Breljak ◽  
Marija Ljubojević ◽  
Daniela Balen ◽  
Vedran Micek ◽  
...  
Keyword(s):  
Rat Kidney ◽  
Organic Anion ◽  
Staining Intensity ◽  
Antigen Retrieval ◽  
Organic Anion Transporters ◽  
Optimal Methods ◽  
Anion Transporters ◽  
Pre Treatment

Optimal Methods of Antigen Retrieval for Organic Anion Transporters in Cryosections of the Rat KidneyTo localise antigens by immunocytochemistry (IC), the samples of tissues or cells are usually denatured by fixation, and either frozen and cryosectioned, or embedded in paraffin before sectioning. p-Formaldehyde (PFA; formalin) is a common fixative, which preserves antigenicity of proteins, but damages the tissue/cell morphology and "masks" the antibody binding sites (epitopes). In order to "unmask" epitopes, some kind of antigen retrieval (AR) is used. The aim of this study was: a) to find an optimal AR method in cryosections of in vivo PFA-fixed kidneys for organic anion transporters (Oat) that reside in the basolateral (Oat1, Oat3) and brush-border membrane (Oat2, Oat5) of the rat renal proximal tubules, and b) using optimal method, to compare IC staining of Oats in kidneys that had been PFA-fixed in vivo or in vitro. IC staining in untreated cryosections was compared with that following detergent treatment or microwave heating in citrate buffer of pH 3, pH 6, or pH 8, with or without alcohol pre-treatment. The preferred AR method for Oat1, Oat2, and Oat5 was heating of cryosections at pH 6, and for Oat3 heating at pH 3, without alcohol pre-treatment. Compared with tissue fixed in vivo, tissue fixed in vitro exhibited damaged tubule morphology, similar staining intensity of Oat1 and Oat3, and higher staining intensity of Oat2 and Oat5. We conclude that for optimal IC presentation, each Oat in the rat kidney has to be treated individually, with different fixation and AR approach.

Sign in / Sign up

Export Citation Format

Share Document