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Generation and Systemic Release
1 The Department of Medicine, University of Washington, Seattle, WA, USA; Fred Hutchinson Cancer Research Center, Seattle, WA, USA
* To whom correspondence should be addressed. E-mail: dzager{at}fhcrc.org.
Background: 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 which can
worsen inflammation and cytotoxicity. Methods: CD-1 mice underwent 15 min of
unilateral renal ischemia. LPS (10 mg/Kg IV), or its vehicle, were injected either 45 min
prior to, or 18 hrs after, the ischemic event. TNF- responses were gauged 2 hrs 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, non ischemic 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 were also
assessed. Results: 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 ~2-5 fold increases in TNF- /
TNF- mRNA. Conclusions: Modest I/R injury, and in vitro HK-2 cell mitochondrial
inhibition (AA), can dramatically sensitize the kidney / proximal tubules, 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.
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