title: Acute renal failure: determinants and characteristics of the injury-induced hyperinflammatory response.
abstract: 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-alpha/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-alpha, 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 ( approximately 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.
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA, USA. dzager@fhcrc.org
authors.forename: Richard A
authors.initials: RA
authors.lastname: Zager
authors.forename: Ali C M
authors.initials: AC
authors.lastname: Johnson
authors.forename: Steve
authors.initials: S
authors.lastname: Lund
authors.forename: Sherry
authors.initials: S
authors.lastname: Hanson
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000503:physiopathology*; D000818:Animals; D018932:Chemokine CCL2 / Q000096:biosynthesis; D002945:Cisplatin; D004731:Endotoxins / Q000494:pharmacology; D005990:Glycerol; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007249:Inflammation / Q000503:physiopathology*; D007668:Kidney / Q000737:chemistry; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D011524:Protoporphyrins / Q000494:pharmacology; D013682:Teichoic Acids / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis; D015854:Up-Regulation
chemical_list: D018932:Chemokine CCL2; D004731:Endotoxins; D008070:Lipopolysaccharides; D008665:Metalloporphyrins; D011524:Protoporphyrins; D013682:Teichoic Acids; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C002744:3-nitrotyrosine; D014443:Tyrosine; C009900:lipoteichoic acid; C032628:tin protoporphyrin IX; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051547:Heme Oxygenase-1; D005990:Glycerol; D002945:Cisplatin