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Am J Physiol Renal Physiol (March 29, 2005). doi:10.1152/ajprenal.00023.2005
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Submitted on January 21, 2005
Accepted on March 22, 2005

Ischemic Proximal Tubular Injury Primes Mice to Endotoxin- Induced TNF-{alpha} Generation and Systemic Release

R A Zager1*, Ali CM Johnson1, Sherry Y Hanson1, and Steve Lund1

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-{alpha} 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-{alpha} responses were gauged 2 hrs post LPS injection by measuring plasma / renal cortical TNF-{alpha}, and renal cortical TNF-{alpha} mRNA. Values were contrasted to those obtained in sham operated mice, or in contralateral, non ischemic kidneys. TNF-{alpha} 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-{alpha} or its mRNA. However, this same ischemic insult dramatically sensitized mice to LPS mediated- TNF-{alpha} increases in both plasma and kidney (~2 fold). During late reperfusion, increased TNF-{alpha} mRNA levels also resulted. PTS generated TNF-{alpha} in response to injury. Neither AA nor LPS alone induced an HK-2 cell TNF-{alpha} response. However, when present together, AA + LPS induced ~2-5 fold increases in TNF-{alpha} / TNF-{alpha} 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-{alpha} generation, and increases in TNF-{alpha} 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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