PMID- 16282336
OWN - NLM
STAT- MEDLINE
DCOM- 20060629
LR  - 20220331
IS  - 0931-0509 (Print)
IS  - 0931-0509 (Linking)
VI  - 21
IP  - 3
DP  - 2006 Mar
TI  - Eicosapentaenoic acid ameliorates diabetic nephropathy of type 2 diabetic KKAy/Ta 
      mice: involvement of MCP-1 suppression and decreased ERK1/2 and p38 
      phosphorylation.
PG  - 605-15
AB  - BACKGROUND: Previous studies reported that eicosapentaenoic acid (EPA) was 
      effective against any renal diseases including diabetic nephropathy. Monocyte 
      chemoattractant protein-1 (MCP-1) is a regulating macrophage recruitment protein, 
      which is up-regulated in patients with diabetic nephropathy. The objectives of 
      the present study were to evaluate the effects of EPA including renal MCP-1 
      expression in diabetic KKAy/Ta mice, MCP-1 production and signal transduction in 
      mouse mesangial cells (MMCs). METHODS: KKAy/Ta mice were injected with EPA ethyl 
      ester (1 g/kg/day) intraperitoneally. Immunohistochemical staining of MCP-1, 
      F4/80, phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2) and 
      phospho-p38 in the renal sections were performed. EPA or specific inhibitors were 
      incorporated in MMCs, and the levels of supernatant MCP-1 were measured. The 
      effect of EPA on ERK1/2, c-jun NH2-terminal kinase (JNK), p38 or phosphoinositide 
      3-kinase (PI3K) activity in MMCs was examined using Western blot. RESULTS: EPA 
      decreased the levels of serum triglycerides, leptin, urinary albumin and MCP-1, 
      and improved glucose intolerance, mesangial matrix accumulation and 
      tubulointerstitial fibrosis in KKAy/Ta mice. Immunohistochemical staining of 
      MCP-1 and F4/80 in the glomeruli and tubulointerstitial regions was decreased in 
      the EPA-treated group. EPA and specific inhibitors of ERK1/2, JNK and PI3K 
      decreased levels of MCP-1 in MMCs. EPA suppressed phosphorylation of ERK1/2 and 
      p38 in MMCs, and decreased p-ERK positive cells in glomeruli of KKAy/Ta mice. 
      CONCLUSIONS: EPA ameliorates diabetic nephropathy of type 2 diabetic KKAy/Ta 
      mice. We propose that the observed down-regulation of MCP-1 is critically 
      involved in the beneficial effect of EPA, probably in concert with improvement of 
      other clinical parameters.
FAU - Hagiwara, Shinji
AU  - Hagiwara S
AD  - Division of Nephrology, Department of Internal Medicine, Juntendo University 
      School of Medicine, 2-1-1 Hongo, Tokyo 113-8421, Japan.
FAU - Makita, Yuichiro
AU  - Makita Y
FAU - Gu, Leyi
AU  - Gu L
FAU - Tanimoto, Mitsuo
AU  - Tanimoto M
FAU - Zhang, Minfang
AU  - Zhang M
FAU - Nakamura, Shinji
AU  - Nakamura S
FAU - Kaneko, Shigeru
AU  - Kaneko S
FAU - Itoh, Takamichi
AU  - Itoh T
FAU - Gohda, Tomohito
AU  - Gohda T
FAU - Horikoshi, Satoshi
AU  - Horikoshi S
FAU - Tomino, Yasuhiko
AU  - Tomino Y
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20051110
PL  - England
TA  - Nephrol Dial Transplant
JT  - Nephrology, dialysis, transplantation : official publication of the European 
      Dialysis and Transplant Association - European Renal Association
JID - 8706402
RN  - 0 (Chemokine CCL2)
RN  - AAN7QOV9EA (Eicosapentaenoic Acid)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Chemokine CCL2/*biosynthesis/drug effects
MH  - Diabetes Mellitus, Type 2/*complications/metabolism
MH  - Diabetic Nephropathies/*drug therapy/etiology/metabolism
MH  - Eicosapentaenoic Acid/*therapeutic use
MH  - Immunohistochemistry
MH  - In Vitro Techniques
MH  - Kidney Glomerulus/drug effects/metabolism/pathology
MH  - Male
MH  - Mesangial Cells/metabolism/pathology
MH  - Mice
MH  - Mice, Obese
MH  - Mitogen-Activated Protein Kinase 1/drug effects/*metabolism
MH  - Phosphorylation/drug effects
MH  - Signal Transduction/drug effects
MH  - Treatment Outcome
MH  - p38 Mitogen-Activated Protein Kinases/drug effects/*metabolism
EDAT- 2005/11/12 09:00
MHDA- 2006/06/30 09:00
CRDT- 2005/11/12 09:00
PHST- 2005/11/12 09:00 [pubmed]
PHST- 2006/06/30 09:00 [medline]
PHST- 2005/11/12 09:00 [entrez]
AID - gfi208 [pii]
AID - 10.1093/ndt/gfi208 [doi]
PST - ppublish
SO  - Nephrol Dial Transplant. 2006 Mar;21(3):605-15. doi: 10.1093/ndt/gfi208. Epub 
      2005 Nov 10.