PMID- 14717919
OWN - NLM
STAT- MEDLINE
DCOM- 20040914
LR  - 20220408
IS  - 0085-2538 (Print)
IS  - 0085-2538 (Linking)
VI  - 65
IP  - 2
DP  - 2004 Feb
TI  - Salicylate reduces cisplatin nephrotoxicity by inhibition of tumor necrosis 
      factor-alpha.
PG  - 490-9
AB  - BACKGROUND: Salicylate was recently shown to provide protection against cisplatin 
      nephrotoxicity in rats. We have demonstrated that enhanced tumor necrosis 
      factor-alpha (TNF-alpha) production mediates, in part, cisplatin nephrotoxicity. 
      The purpose of this study was to determine if the protective effects of 
      salicylate were mediated through inhibition of TNF-alpha in vivo and to explore 
      the mechanism of inhibition in vitro. METHODS: The effects of treatment with 
      cisplatin alone and in combination with sodium salicylate in mice on renal 
      function, histology, and gene expression were determined. The effects of 
      cisplatin and salicylate on TNF-alpha expression, nuclear factor kappa B 
      (NF-kappa B) activity, and apoptosis were determined in vitro using cultured 
      murine proximal tubule cells. RESULTS: Salicylate significantly reduced both the 
      functional and histologic evidence of cisplatin renal injury. Cisplatin increased 
      the renal expression of TNF-alpha, monocyte chemoattractant protein-1 (MCP-1), 
      intercellular adhesion molecule (ICAM)-1, heme oxygenase-1, TNF receptor 1 
      (TNFR1), and TNF receptor 2 (TNFR2). Treatment with sodium salicylate blunted the 
      increase in TNF-alpha mRNA and also reduced serum TNF-alpha protein levels. 
      Salicylate had little protective effect when administered with cisplatin to 
      TNF-alpha-deficient mice. Cisplatin increased the degradation of I kappa B (I 
      kappa B) in a time-dependent manner and also increased nuclear NF-kappa B binding 
      activity. Salicylate inhibited I kappa B degradation and NF-kappa B binding 
      activity in the presence of cisplatin. In addition, salicylate inhibited the 
      cisplatin induced TNF-alpha mRNA increase in mouse proximal tubule epithelial 
      (TKPT) cells. CONCLUSION: These results indicate that salicylate acts via 
      inhibition of TNF-alpha production to reduce cisplatin nephrotoxicity. The 
      inhibition of TNF-alpha production may be mediated via stabilization of I kappa 
      B.
FAU - Ramesh, Ganesan
AU  - Ramesh G
AD  - Division of Nephrology, The Penn State College of Medicine, Hershey, Pennsylvania 
      17033, USA.
FAU - Reeves, W Brian
AU  - Reeves WB
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Kidney Int
JT  - Kidney international
JID - 0323470
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (I-kappa B Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (Receptors, Tumor Necrosis Factor)
RN  - 0 (Salicylates)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 126547-89-5 (Intercellular Adhesion Molecule-1)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents, Non-Steroidal/*pharmacology
MH  - Antineoplastic Agents/*toxicity
MH  - Apoptosis/drug effects
MH  - Cisplatin/*toxicity
MH  - Drug Interactions
MH  - Gene Expression/drug effects
MH  - I-kappa B Proteins/metabolism
MH  - Intercellular Adhesion Molecule-1/genetics
MH  - Kidney Diseases/chemically induced/*drug therapy/physiopathology
MH  - Kidney Tubules, Proximal/drug effects/physiology
MH  - Leukocytes/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Mutant Strains
MH  - NF-kappa B/metabolism
MH  - Receptors, Tumor Necrosis Factor/genetics
MH  - Salicylates/*pharmacology
MH  - Tumor Necrosis Factor-alpha/*genetics/metabolism
MH  - Up-Regulation
EDAT- 2004/01/14 05:00
MHDA- 2004/09/15 05:00
CRDT- 2004/01/14 05:00
PHST- 2004/01/14 05:00 [pubmed]
PHST- 2004/09/15 05:00 [medline]
PHST- 2004/01/14 05:00 [entrez]
AID - S0085-2538(15)49731-5 [pii]
AID - 10.1111/j.1523-1755.2004.00413.x [doi]
PST - ppublish
SO  - Kidney Int. 2004 Feb;65(2):490-9. doi: 10.1111/j.1523-1755.2004.00413.x.