Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) increase sulfate renal clearance and decrease the fractional reabsorption of sulfate by the kidneys. The mechanism of this alteration of inorganic sulfate homeostasis is unknown. The objectives of this study were 1) to investigate if sulfate renal transport is altered in isolated membrane vesicles after pretreatment of animals in vivo with ibuprofen (IBU), and 2) to determine the cellular mechanism of changes in sulfate renal transport. Female Lewis rats received IBU at a i.v. dose of 27 mg/kg followed by an infusion of 33 μg/min for 4 hr. Sulfate transport was studied using brush border (BBM) and basolateral membrane (BLM) vesicles isolated from rat kidney cortex. TheVmax for the sodium-dependent sulfate cotransport (NaSi-1) in BBM was significantly lower in the IBU group compared with the control group (0.79 ± 0.23 vs. 1.25 ± 0.17 nmol/mg protein/10 sec, respectively; P < .05) with no change in Km. There were no significant differences between the study groups in sulfate anion exchange kinetics in BLM vesicles. NaSi-1 transporter mRNA level in kidney cortex and protein level in BBM were significantly lower in animals pretreated with IBU compared with that in control animals. There was no change in membrane fluidity of BBM and BLM isolated from IBU-treated animals as measured by the fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene. These results indicate that IBU treatment alters sodium-dependent sulfate cotransport by a downregulation of mRNA and protein of NaSi-1 transporter in BBM.
Footnotes
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Send reprint requests to: Marilyn E. Morris, Ph.D., 527 Hochstetter Hall, Department of Pharmaceutics, State University of New York at Buffalo, Amherst, NY 14260. E-mail: memorris{at}acsu.buffalo.edu
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↵1 This work was supported by NIH grant GM-40551, NSF grant IBN 9629470, and grants from the Western New York Kidney Foundation/Upstate NY Transplant Services and the Kapoor Charitable Foundation at SUNY at Buffalo (for MEM), and Swiss National Science Foundation (for HM). LJB was supported in part by a graduate fellowship from the American Foundation for Pharmaceutical Education. We thank Dr. S.V. Balasubramanian (SUNY at Buffalo) for performing the fluorescence polarization studies, and Dr. Richard R. Almon and Dr. Debra C. DuBois (SUNY at Buffalo) for their advice and guidance with the RT-PCR and ELISA assays.
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↵2 Present address: SmithKline Beecham, 709 Swedeland Road, King of Prussia, PA 19406-0939.
- Abbreviations:
- NSAID
- nonsteroidal anti-inflammatory drug
- BBM
- brush border membrane
- BLM
- basolateral membrane
- IBU
- ibuprofen
- mRNA
- messenger RNA
- RT-PCR
- reverse transcriptase-polymerase chain reaction
- ELISA
- enzyme-linked immunosorbent assay
- DPH
- 1,6-diphenyl-1,3,5-hexatriene
- PGE2
- prostaglandin E2
- cAMP
- cyclic AMP
- Received May 15, 1998.
- Accepted July 13, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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