Abstract
Although dietary fish oil supplementation has been used to prevent the progression
of kidney disease in patients with IgA nephropathy, relatively few studies provide
a mechanistic rationale for its use. Using an antithymocyte (ATS) model of mesangial
proliferative glomerulonephritis, we recently demonstrated that fish oil inhibits
mesangial cell (MC) activation and proliferation, reduces proteinuria, and decreases
histologic evidence of glomerular damage. We therefore sought to define potential
mechanisms underlying the antiproliferative effect of docosahexaenoic acid (DHA) and
eicosapentaenoic acid (EPA), the predominant ω-3 polyunsaturated fatty acids
found in fish oil, in cultured MC. DHA and EPA were administered to MC as bovine serum
albumin fatty-acid complexes. Low-dose (10-50 μmol/L) DHA, but not EPA, inhibited
basal and epidermal growth factor (EGF)–stimulated [3H]-thymidine incorporation in MCs. At higher doses (100 μmol/L), EPA and DHA
were equally effective in suppressing basal and EGF-stimulated MC mitogenesis. Low-dose
DHA, but not EPA, decreased ERK activation by 30% (P < .01), as assessed with Western-blot analysis using phosphospecific antibodies.
JNK activity was increased by low-dose DHA but not by EPA. p38 activity was not significantly
altered by DHA or EPA. Cyclin E activity, as assessed with a histone H1 kinase assay,
was inhibited by low-dose DHA but not by EPA. DHA increased expression of the cell
cycle inhibitor p21 but not p27; EPA had no effect on p21 or p27. We propose that
the differential effect of low-dose DHA vs EPA in suppressing MC mitogenesis is related
to down-regulation of ERK and cyclin E activity and to induction of p21.
Keywords:
ATS (antithymocyte serum), BSA (bovine serum albumin), DHA (docosahexaenoic acid), ECL (enhanced chemiluminescence), EDTA (ethylenediaminetetraacetic acid), EGF (epidermal growth factor), EPA (eicosapentaenoic acid), HEPES (N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid), IL-6 (interleukin-6), ITS+ (insulin, transferrin, selenium, and BSA), LDH (lactate dehydrogenase), MAPK (mitogen-activated protein kinases), MC (mesangial cells), PBS (phosphate-buffered saline solution), PDGF (platelet-derived growth factor), PMSF (phenylmethylsulfonylfluoride), pRb (retinoblastoma protein), ω-3 PUFA (ω-3 polyunsaturated fatty acid), RIPA (PBS, 1% Nonidet P-40, 0.5% sodium deoxycholate, 0.1% SDS, 100 μg/mL PMSF, 2 μg/mL aprotinin, and 200 μmol/L sodium orthovanidate), SDS-PAGE (sodium dodecyl sulfate–polyacrylamide gel electrophoresis), TBS (Tris-buffered saline solution), TCA (trichloroacetic acid), TdT (terminal deoxynucleotidyl transferase), TNF (tumor necrosis factor), VSMC (vascular smooth muscle cells)To read this article in full you will need to make a payment
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Article info
Publication history
Accepted:
December 9,
2002
Received in revised form:
December 1,
2002
Received:
August 15,
2002
Footnotes
Supported by National Institutes of Health grants DK16105 and 55603.
Identification
Copyright
© 2003 Elsevier Science Inc. Published by Elsevier Inc. All rights reserved.
