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Regulation of Renal Organic Ion Transporters in Cisplatin-Induced Acute Kidney Injury and Uremia in Rats

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Abstract

Purpose

The purpose of this study was to examine the regulation of renal organic ion transporters in cisplatin-induced acute kidney injury (AKI) and its relation with indoxyl sulfate (IS), a uremic toxin.

Methods

The IS concentrations in the serum and kidney were monitored by high-performance liquid chromatography. Uptake of p-aminohippuric acid, estrone-3-sulfate and tetraethylammonium were examined using renal slices. Real-time PCR and immunoblotting were performed to examine the mRNA and protein expression of rOATs, rOCTs and rMATE1 in the kidney, respectively.

Results

The serum and renal IS levels were markedly elevated in cisplatin-treated rats. However, this effect was largely reversed by administration of AST-120, an oral charcoal adsorbent. The functions of renal basolateral organic anion and cation transporters were reduced in cisplatin-treated rats. The levels of mRNA and protein corresponding to rOAT1, rOAT3, rOCT2 and rMATE1, but not rOCT1, were depressed in the kidney of cisplatin-treated rats. Administration of AST-120 to cisplatin-treated rats partially restored the function and expression level of these transporters.

Conclusions

Cisplatin-induced AKI causes down-regulation of renal organic ion transporters accompanied by accumulation of serum and renal IS. IS could be involved in the mechanism of down-regulation of rOAT1, rOAT3 and rMATE1 under cisplatin-induced AKI.

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Abbreviations

AKI:

acute kidney injury

BUN:

blood urea nitrogen

ES:

estrone-3-sulfate

IS:

indoxyl sulfate

MATE:

multidrug and toxin extrusion

OAT:

organic anion transporter

OCT:

organic cation transporter

PAH:

p-aminohippuric acid

SCr:

serum creatinine

TEA:

tetraethylammonium

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Acknowledgments

This work was supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS) for Hideyuki Saito (KAKENHI 17390158) and Akinobu Hamada (KAKENHI 19590149).

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Correspondence to Hideyuki Saito.

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Morisaki, T., Matsuzaki, T., Yokoo, K. et al. Regulation of Renal Organic Ion Transporters in Cisplatin-Induced Acute Kidney Injury and Uremia in Rats. Pharm Res 25, 2526–2533 (2008). https://doi.org/10.1007/s11095-008-9668-2

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  • DOI: https://doi.org/10.1007/s11095-008-9668-2

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