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IL-1 receptor blockade alleviates endotoxin-mediated impairment of renal drug excretory functions in rats
Z. Kadova, E. Dolezelova, J. Cermanova, M. Hroch, T. Laho, L. Muchova, F. Staud, L. Vitek, J. Mokry, J. Chladek, Z. Havlinova, M. Holecek, S. Micuda,
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
NLK
Open Access Digital Library
from 1997-10-01
Open Access Digital Library
from 1998-01-01
- MeSH
- Acute Kidney Injury etiology prevention & control MeSH
- Interleukin 1 Receptor Antagonist Protein pharmacology therapeutic use MeSH
- Anti-Bacterial Agents pharmacokinetics MeSH
- Anti-Inflammatory Agents pharmacology therapeutic use MeSH
- Azithromycin pharmacokinetics MeSH
- Dexamethasone pharmacology therapeutic use MeSH
- Renal Elimination drug effects MeSH
- Endotoxemia complications drug therapy MeSH
- Endotoxins pharmacokinetics MeSH
- Glomerular Filtration Rate drug effects MeSH
- Immunosuppressive Agents pharmacology therapeutic use MeSH
- Lipopolysaccharides MeSH
- Rats, Wistar MeSH
- Xenobiotics pharmacokinetics MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
The aim of our study was to investigate whether two potent anti-inflammatory agents, dexamethasone and anakinra, an IL-1 receptor antagonist, may influence acute kidney injury (AKI) and associated drug excretory functions during endotoxemia (LPS) in rats. Ten hours after LPS administration, untreated endotoxemic rats developed typical symptoms of AKI, with reduced GFR, impaired tubular excretion of urea and sodium, and decreased urinary excretion of azithromycin, an anionic substrate for multidrug resistance-transporting proteins. Administration of both immunosuppressants attenuated the inflammatory response, liver damage, AKI, and increased renal clearance of azithromycin mainly by restoration of GFR, without significant influence on its tubular secretion. The lack of such an effect was related to the differential effect of both agents on the renal expression of individual drug transporters. Only dexamethasone increased the urinary clearance of bile acids, in accordance with the reduction of the apical transporter (Asbt) for their tubular reabsorption. In summary, our data demonstrated the potency of both agents used for the prevention of AKI, imposed by endotoxins, and for the restoration of renal drug elimination, mainly by the improvement of GFR. The influence of both drugs on altered tubular functions and the expression of drug transporters was differential, emphasizing the necessity of knowledge of transporting pathways for individual drugs applied during sepsis. The effect of anakinra suggests a significant contribution of IL-1 signaling to the pathogenesis of LPS-induced AKI.
References provided by Crossref.org
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- $a Kadova, Zuzana $u Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic; Department of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Hradec Kralove, Czech Republic;
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- $a The aim of our study was to investigate whether two potent anti-inflammatory agents, dexamethasone and anakinra, an IL-1 receptor antagonist, may influence acute kidney injury (AKI) and associated drug excretory functions during endotoxemia (LPS) in rats. Ten hours after LPS administration, untreated endotoxemic rats developed typical symptoms of AKI, with reduced GFR, impaired tubular excretion of urea and sodium, and decreased urinary excretion of azithromycin, an anionic substrate for multidrug resistance-transporting proteins. Administration of both immunosuppressants attenuated the inflammatory response, liver damage, AKI, and increased renal clearance of azithromycin mainly by restoration of GFR, without significant influence on its tubular secretion. The lack of such an effect was related to the differential effect of both agents on the renal expression of individual drug transporters. Only dexamethasone increased the urinary clearance of bile acids, in accordance with the reduction of the apical transporter (Asbt) for their tubular reabsorption. In summary, our data demonstrated the potency of both agents used for the prevention of AKI, imposed by endotoxins, and for the restoration of renal drug elimination, mainly by the improvement of GFR. The influence of both drugs on altered tubular functions and the expression of drug transporters was differential, emphasizing the necessity of knowledge of transporting pathways for individual drugs applied during sepsis. The effect of anakinra suggests a significant contribution of IL-1 signaling to the pathogenesis of LPS-induced AKI.
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