Acute nephrotoxic and obstructive injury primes the kidney to endotoxin-driven cytokine/chemokine production

Kidney Int. 2006 Apr;69(7):1181-8. doi: 10.1038/sj.ki.5000022.

Abstract

Gram-negative sepsis is a frequent complication in patients with acute renal failure. This study tested whether acute tubular injury, for example, induced by cisplatin (CP) or urinary tract obstruction, enhances renal cytokine responses to endotoxin (lipopolysaccharide (LPS)), potentially contributing to tissue damage. CD-1 mice were subjected to CP or vehicle injection. After 24 or 72 h, LPS or its vehicle was given. At 2 h post LPS or vehicle administration, plasma/renal cortical tumor necrosis factor (TNF)-alpha, monocyte chemoattractant protein-1 (MCP-1), and interleukin-10, and their corresponding renal cortical mRNAs were assessed (representing pro-anti-inflammatory cytokines, and a chemokine, respectively). Comparable studies were conducted in mice 24 h post unilateral ureteral obstruction (UUO). Cultured human proximal tubular (HK-2) cell TNF-alpha responses to CP+/-LPS were also assessed. CP alone caused either minimal or no increases in cytokine levels. However, CP dramatically augmented cytokine responses to LPS (up to 5-10 x vs LPS alone). The cytokine increases were paralleled by changes in their mRNAs. UUO also sensitized to LPS. CP alone did not alter HK-2 cell TNF-alpha/mRNA. However, CP 'primed' the cells to LPS (approximately 50-100% greater TNF-alpha/mRNA increases vs LPS alone). CP+LPS also caused synergistic cell death (lactate dehydrogenase release). We conclude that (1) diverse forms of tubular injury can sensitize the kidney to LPS, increasing cytokine production; (2) proximal tubules are involved; (3) LPS 'priming' has broad-based consequences, impacting diverse pro- and anti-inflammatory pathways; and (4) increased transcriptional events may be at least partially involved.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Kidney Injury / chemically induced
  • Acute Kidney Injury / pathology
  • Animals
  • Cells, Cultured
  • Chemokine CCL2 / pharmacology
  • Chemokines / genetics*
  • Cisplatin / toxicity*
  • Cytokines / genetics*
  • Endotoxins / toxicity*
  • Humans
  • Interleukin-10 / pharmacology
  • Kidney / drug effects
  • Kidney / injuries*
  • Kidney / pathology*
  • Kidney Tubules, Proximal / drug effects
  • L-Lactate Dehydrogenase
  • Male
  • Mice
  • RNA, Messenger / genetics
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Chemokines
  • Cytokines
  • Endotoxins
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • L-Lactate Dehydrogenase
  • Cisplatin