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: 291/3/F546    most recent 00072.2006v1 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 ISI 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 ISI Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Zager, R. A. Articles by Hanson, S. Search for Related Content PubMed PubMed Citation Articles by Zager, R. A. Articles by Hanson, S.

Acute renal failure: determinants and characteristics of the injury-induced hyperinflammatory response

¹Department of Medicine, University of Washington, and the ²Fred Hutchinson Cancer Research Center, Seattle, Washington

Submitted 28 February 2006 ; accepted in final form 19 April 2006

Acute renal failure (ARF) markedly sensitizes mice to endotoxin (LPS), as evidenced by exaggerated renal cytokine/chemokine production. This study sought to further characterize this state by testing the following: 1) does anti-inflammatory heme oxygenase-1 (HO-1) upregulation in selected ARF models prevent this response? 2) Is the ARF hyperresponsive state specifically triggered by LPS? 3) Does excess iNOS activity/protein nitrosylation participate in this phenomenon? and 4) are upregulated Toll receptors involved? Mice with either 1) rhabdomyolysis-induced ARF (massive HO-1 overexpression), 2) cisplatin nephrotoxicity, 3) or HO-1 inhibition (Sn protoporphyrin) were challenged with either LPS (a TLR4 ligand), lipoteichoic acid (LTA; a TLR2 ligand), or vehicle. Two hours later, renal and plasma TNF-/mRNA, MCP-1/mRNA, renal nitrotyrosine/iNOS mRNA, and plasma cytokines were assessed. Renal TLR4 was gauged by mRNA and Western blot analysis. Both ARF models markedly hyperresponded to both LPS and LTA, culminating in exaggerated TNF-, MCP-1, and iNOS/nitrotryosine increments. This was despite the fact that HO-1 exerted anti-inflammatory effects. TLR4 levels were either normal (cisplatin), or markedly depressed (50%; rhabdomyolysis) in the ARF kidneys, despite the LPS hyperresponsive state. 1) The ARF kidney can hyperrespond to chemically dissimilar Toll ligands; 2) HO-1 does not prevent this response; 3) excess NO/protein nitrosylation can result; and 4) this hyperresponsiveness can be expressed with either normal or reduced renal TLR4 expression. This suggests that diverse signaling pathways may be involved.

endotoxin; lipoteichoic acid; iNOS; tumor necrosis factor-; monocyte chemoattractant protein-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]

				R. A. Zager "Subclinical" gentamicin nephrotoxicity: a potential risk factor for exaggerated endotoxin-driven TNF-{alpha} production Am J Physiol Renal Physiol, July 1, 2007; 293(1): F43 - F49. [Abstract] [Full Text] [PDF]

				S. Bolisetty and A. Agarwal Subclinical kidney injury incites endotoxin hyperresponsiveness Am J Physiol Renal Physiol, July 1, 2007; 293(1): F41 - F42. [Full Text] [PDF]

				G. Ramesh, B. Zhang, S. Uematsu, S. Akira, and W. B. Reeves Endotoxin and cisplatin synergistically induce renal dysfunction and cytokine production in mice Am J Physiol Renal Physiol, July 1, 2007; 293(1): F325 - F332. [Abstract] [Full Text] [PDF]

				R. A. Zager, A. C. M. Johnson, S. Lund, and J. Randolph-Habecker Toll-like receptor (TLR4) shedding and depletion: acute proximal tubular cell responses to hypoxic and toxic injury Am J Physiol Renal Physiol, January 1, 2007; 292(1): F304 - F312. [Abstract] [Full Text] [PDF]