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1 Medicine, University of Washington, Seattle, Washington, United States; Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States
2 Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States
* To whom correspondence should be addressed. E-mail: dzager{at}fhcrc.org.
Background: 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) up-regulation in selected ARF models prevent this response? 2) Is the ARF- hyper-responsive state specifically triggered by LPS? 3) Does excess iNOS activity / protein nitrosylation participate in this phenomenon? and 4) Are up-regulated Toll receptors involved?
Methods: Mice with either: i) rhabdomyolysis- induced ARF (massive HO-1 over-expression); ii), cisplatin nephrotoxicity, iii) or HO-1 inhibition (Sn protoporphyrin) were challenged with either LPS (a TLR4 ligand), lipoteichoic acid (LTA; a TLR2 ligand), or vehicle. Two hrs 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.
Results: Both ARF models markedly hyper-responded 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 hyper-responsive state.
Conclusions: 1) The ARF kidney can hyper-respond to chemically dissimilar Toll ligands; 2) HO-1 does not prevent this response; 3) excess NO / protein nitrosylation can result; and 4) this hyper-responsiveness can be expressed with either normal or reduced renal TLR4 expression. This suggests that diverse signaling pathways may be involved.
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