HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 293/1/F43    most recent 00144.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Zager, R. A. Search for Related Content PubMed PubMed Citation Articles by Zager, R. A.

EDITORIAL FOCUS

"Subclinical" gentamicin nephrotoxicity: a potential risk factor for exaggerated endotoxin-driven TNF- production

Department of Medicine, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, Washington

Submitted 27 March 2007 ; accepted in final form 16 April 2007

This study sought to determine whether gentamicin, a mainstay in treating Gram-negative sepsis, alters endotoxin (lipopolysaccharide; LPS)-driven TNF- increases. CD-1 mice received 1 day of gentamicin treatment. Either 0, 24, or 72 h later, gentamicin-treated and control mice were injected with LPS. Renal cortical and plasma TNF-, as well as MCP-1, protein levels were measured 2 or 24 h post-LPS injection. Renal cortical mRNAs for TNF-, MCP-1, IL-10, and inducible nitric oxide synthase (iNOS) were also determined. Finally, gentamicin's potential impact(s) on TNF-/MCP-1 mRNA levels in nontraditional "target" organs (liver, spleen) was assessed. Gentamicin, when administered alone, slightly increased renal cortical TNF- and MCP-1 mRNAs, but without changing plasma or renal TNF-/MCP-1 protein levels. The gentamicin protocol induced no overt renal damage (assessed by blood urea nitrogen, creatinine, and histology). Nevertheless, gentamicin augmented LPS responsiveness, as manifested, in part, by a doubling of LPS-induced plasma TNF- increases (vs. LPS injection alone). Plasma and renal cortical MCP-1 protein levels were also selectively enhanced. Gentamicin augmented LPS-driven renal mRNA increases (TNF-, MCP-1, IL-10, iNOS). However, this was not an entirely renal-specific response, since gentamicin also enhanced basal and LPS-stimulated hepatic TNF- mRNA levels. Subclinical gentamicin toxicity can potentiate LPS-driven TNF- increases. Alterations in multiple proinflammatory (TNF-; MCP-1; iNOS) and anti-inflammatory (IL-10) genes in the kidney, and possibly in extrarenal organs, may be involved. Thus gentamicin's activity in Gram-negative sepsis may extend beyond its traditional antimicrobial effect.

aminoglycosides; sepsis; kidney; proximal tubules; MCP-1

This article has been cited by other articles:

				R. A. Zager, A. C. M. Johnson, and A. Geballe Gentamicin suppresses endotoxin-driven TNF-{alpha} production in human and mouse proximal tubule cells Am J Physiol Renal Physiol, October 1, 2007; 293(4): F1373 - F1380. [Abstract] [Full Text] [PDF]