PMID- 12472797
OWN - NLM
STAT- MEDLINE
DCOM- 20040302
LR  - 20220318
IS  - 0085-2538 (Print)
IS  - 0085-2538 (Linking)
VI  - 63
IP  - 1
DP  - 2003 Jan
TI  - Inhibition of nuclear factor-kappaB activation by pyrrolidine dithiocarbamate 
      prevents chronic FK506 nephropathy.
PG  - 306-14
AB  - BACKGROUND: Chronic tacrolimus (FK506) nephrotoxicity is characterized by renal 
      fibrosis with interstitial inflammation. Since nuclear factor-kappaB (NF-kappaB) 
      plays a key role in chronic inflammatory diseases including renal disease, the 
      present study was conducted to elucidate the role of NF-kappaB in the 
      pathogenesis of chronic FK506-induced nephropathy. METHODS: FK506 (1 mg/kg/day, 
      SC) was administered daily to rats maintained on low sodium diet for 42 days. 
      Some rats were treated with a putative NF-kappaB inhibitor, pyrrolidine 
      dithiocarbamate (PDTC; 100, 200 mg/kg/day, by gavage). The renal function, renal 
      histology, renal NF-kappaB-DNA binding activity and gene expression profile were 
      examined. RESULTS: FK506 caused a decline in glomerular filtration and induced 
      characteristic renal morphologic changes including arteriolopathy, tubular 
      atrophy and interstitial fibrosis. FK506 markedly activated renal cortical 
      NF-kappaB-DNA binding. PDTC administration inhibited NF-kappaB-DNA binding 
      activity in a dose dependent manner. With higher dose, NF-kappaB-DNA binding 
      activity was decreased to a control level. PDTC had little effect on 
      FK506-induced renal dysfunction. Renal cortical monocyte/macrophage infiltration 
      observed in FK506-treated rats was dramatically suppressed by PDTC. FK506 
      up-regulated renal cortical gene expression of chemoattractant proteins, monocyte 
      chemoattractant protein-1 (MCP-1) and osteopontin. PDTC significantly blocked 
      MCP-1 gene expression but had no effect on osteopontin gene expression. Tubular 
      atrophy and tubulointerstitial fibrosis, but not arteriolopathy, were 
      significantly attenuated by PDTC. FK506 increased renal mRNA expression of 
      fibrogenic molecules and extracellular matrices that also were attenuated by PDTC 
      treatment. CONCLUSIONS: NF-kappaB plays an important role in mediating cortical 
      monocyte/macrophage infiltration and in the pathogenesis of tubular injury and 
      interstitial fibrosis in experimental FK506-induced chronic nephropathy.
FAU - Tamada, Satoshi
AU  - Tamada S
AD  - Department of Urology, Osaka City University, Osaka, Japan.
FAU - Nakatani, Tatsuya
AU  - Nakatani T
FAU - Asai, Toshihiro
AU  - Asai T
FAU - Tashiro, Koichiro
AU  - Tashiro K
FAU - Komiya, Toshiyuki
AU  - Komiya T
FAU - Sumi, Tomohiko
AU  - Sumi T
FAU - Okamura, Mikio
AU  - Okamura M
FAU - Kim, Shokei
AU  - Kim S
FAU - Iwao, Hiroshi
AU  - Iwao H
FAU - Kishimoto, Taketoshi
AU  - Kishimoto T
FAU - Yamanaka, Shinya
AU  - Yamanaka S
FAU - Miura, Katsuyuki
AU  - Miura K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Kidney Int
JT  - Kidney international
JID - 0323470
RN  - 0 (Chemokine CCL2)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (NF-kappa B)
RN  - 0 (Pyrrolidines)
RN  - 0 (RNA, Messenger)
RN  - 0 (Sialoglycoproteins)
RN  - 0 (Spp1 protein, rat)
RN  - 0 (Thiocarbamates)
RN  - 106441-73-0 (Osteopontin)
RN  - 25769-03-3 (pyrrolidine dithiocarbamic acid)
RN  - WM0HAQ4WNM (Tacrolimus)
SB  - IM
MH  - Animals
MH  - Chemokine CCL2/genetics
MH  - Chronic Disease
MH  - Electrophoretic Mobility Shift Assay
MH  - Immunohistochemistry
MH  - Immunosuppressive Agents/*toxicity
MH  - Kidney/metabolism/pathology
MH  - Kidney Diseases/chemically induced/drug therapy/*prevention & control
MH  - Macrophages/drug effects/pathology
MH  - Male
MH  - Monocytes/drug effects/pathology
MH  - NF-kappa B/*metabolism
MH  - Osteopontin
MH  - Pyrrolidines/*metabolism
MH  - RNA, Messenger/analysis
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Sialoglycoproteins/genetics
MH  - Tacrolimus/*toxicity
MH  - Thiocarbamates/*metabolism
EDAT- 2002/12/11 04:00
MHDA- 2004/03/03 05:00
CRDT- 2002/12/11 04:00
PHST- 2002/12/11 04:00 [pubmed]
PHST- 2004/03/03 05:00 [medline]
PHST- 2002/12/11 04:00 [entrez]
AID - S0085-2538(15)48873-8 [pii]
AID - 10.1046/j.1523-1755.2003.00714.x [doi]
PST - ppublish
SO  - Kidney Int. 2003 Jan;63(1):306-14. doi: 10.1046/j.1523-1755.2003.00714.x.