{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T13:43:18Z","timestamp":1772804598704,"version":"3.50.1"},"reference-count":34,"publisher":"American Physiological Society","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Renal Physiology"],"published-print":{"date-parts":[[2005,8]]},"abstract":"<jats:p> 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-\u03b1 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-\u03b1 responses were gauged 2 h post-LPS injection by measuring plasma\/renal cortical TNF-\u03b1 and renal cortical TNF-\u03b1 mRNA. Values were contrasted to those obtained in sham-operated mice or in contralateral, nonischemic kidneys. TNF-\u03b1 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-\u03b1 or its mRNA. However, this same ischemic insult dramatically sensitized mice to LPS-mediated TNF-\u03b1 increases in both plasma and kidney (\u223c2-fold). During late reperfusion, increased TNF-\u03b1 mRNA levels also resulted. PTs generated TNF-\u03b1 in response to injury. Neither AA nor LPS alone induced an HK-2 cell TNF-\u03b1 response. However, when present together, AA+LPS induced approximately two- to fivefold increases in TNF-\u03b1\/TNF-\u03b1 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-\u03b1 generation and increases in TNF-\u03b1 mRNA. That ischemia can \u201cprime\u201d tubules to LPS response(s) could have potentially important implications for sepsis syndrome, concomitant renal ischemia, and for the induction of ARF. <\/jats:p>","DOI":"10.1152\/ajprenal.00023.2005","type":"journal-article","created":{"date-parts":[[2005,3,30]],"date-time":"2005-03-30T01:33:56Z","timestamp":1112146436000},"page":"F289-F297","source":"Crossref","is-referenced-by-count":61,"title":["Ischemic proximal tubular injury primes mice to endotoxin-induced TNF-\u03b1 generation and systemic release"],"prefix":"10.1152","volume":"289","author":[{"given":"R. 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