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generation and systemic release
Department of Medicine, University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle, Washington
Submitted 21 January 2005 ; accepted in final form 22 March 2005
Endotoxemia (LPS) can exacerbate ischemic tubular injury and acute renal failure (ARF). The present study tested the following hypothesis: that acute ischemic damage sensitizes the kidney to LPS-mediated TNF-
generation, a process that can worsen inflammation and cytotoxicity. CD-1 mice underwent 15 min of unilateral renal ischemia. LPS (10 mg/kg iv), or its vehicle, was injected either 45 min before, or 18 h after, the ischemic event. TNF- responses were gauged 2 h post-LPS injection by measuring plasma/renal cortical TNF- and renal cortical TNF- mRNA. Values were contrasted to those obtained in sham-operated mice or in contralateral, nonischemic kidneys. TNF- generation by isolated mouse proximal tubules (PTs), and by cultured proximal tubule (HK-2) cells, in response to hypoxia-reoxygenation (H/R), oxidant stress, antimycin A (AA), or LPS was also assessed. Ischemia-reperfusion (I/R), by itself, did not raise plasma or renal cortical TNF- or its mRNA. However, this same ischemic insult dramatically sensitized mice to LPS-mediated TNF- increases in both plasma and kidney (
2-fold). During late reperfusion, increased TNF- mRNA levels also resulted. PTs generated TNF- in response to injury. Neither AA nor LPS alone induced an HK-2 cell TNF- response. However, when present together, AA+LPS induced approximately two- to fivefold increases in TNF-/TNF- mRNA. We conclude that modest I/R injury, and in vitro HK-2 cell mitochondrial inhibition (AA), can dramatically sensitize the kidney/PTs to LPS-mediated TNF- generation and increases in TNF- mRNA. That ischemia can "prime" tubules to LPS response(s) could have potentially important implications for sepsis syndrome, concomitant renal ischemia, and for the induction of ARF.
tumor necrosis factor; HK-2 cells; proximal tubules; sepsis syndrome; antimycin A
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