title: IL-1 receptor blockade alleviates endotoxin-mediated impairment of renal drug excretory functions in rats.
abstract: 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.
authors.affiliation: 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;
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Kadova
authors.affiliation: Department of Biological and Medical Sciences, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Hradec Kralove, Czech Republic;
authors.forename: Eva
authors.initials: E
authors.lastname: Dolezelova
authors.affiliation: Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic;
authors.forename: Jolana
authors.initials: J
authors.lastname: Cermanova
authors.affiliation: Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic; Department of Medical Biochemistry, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic;
authors.forename: Milos
authors.initials: M
authors.lastname: Hroch
authors.affiliation: Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic;
authors.forename: Tomas
authors.initials: T
authors.lastname: Laho
authors.affiliation: Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic; and.
authors.forename: Lucie
authors.initials: L
authors.lastname: Muchova
authors.affiliation: Department of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Hradec Kralove, Czech Republic;
authors.forename: Frantisek
authors.initials: F
authors.lastname: Staud
authors.affiliation: Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic; and 4th Department of Internal Medicine, 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Libor
authors.initials: L
authors.lastname: Vitek
authors.affiliation: Department of Histology and Embryology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic;
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Mokry
authors.affiliation: Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic;
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Chladek
authors.affiliation: Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic;
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Havlinova
authors.affiliation: Department of Physiology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic;
authors.forename: Milan
authors.initials: M
authors.lastname: Holecek
authors.affiliation: Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic; micuda@lfhk.cuni.cz.
authors.forename: Stanislav
authors.identifier: http://orcid.org/0000-0002-7773-7161
authors.initials: S
authors.lastname: Micuda
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000517:prevention & control*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017963:Azithromycin / Q000493:pharmacokinetics; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use*; D019446:Endotoxemia / Q000150:complications / Q000188:drug therapy; D004731:Endotoxins / Q000493:pharmacokinetics; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology / Q000627:therapeutic use*; D008070:Lipopolysaccharides; D008297:Male; D017208:Rats, Wistar; D065667:Renal Elimination / Q000187:drug effects*; D015262:Xenobiotics / Q000493:pharmacokinetics
chemical_list: D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D004731:Endotoxins; D007166:Immunosuppressive Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D008070:Lipopolysaccharides; D015262:Xenobiotics; D003907:Dexamethasone; D017963:Azithromycin
keywords: acute kidney injury; anakinra; dexamethasone; drug transporters; endotoxins