Eicosapentaenoic acid inhibits PDGF‐induced mitogenesis and cyclin D1 expression via TGF‐β in mesangial cells

Abstract

Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid derived from fish oil, is efficacious in glomerular diseases where mesangial proliferation is a key event. We examined the mechanisms of action of EPA on platelet-derived growth factor (PDGF)-stimulated rat mesangial cell mitogenesis. EPA dose-dependently inhibited PDGF-stimulated [(3)H]-thymidine incorporation. PDGF-induced PDGF receptor autophosphorylation, an initial event for PDGF signaling, was not affected by 2 micro g/ml EPA. Similarly, PDGF-stimulated activation of extracellular signal-regulated kinase (ERK) was not altered. On the other hand, EPA inhibited cyclin-dependent kinase 4 (CDK4) activation and cyclin D1 protein induction, a critical step for G1/S progression. TGF-beta secretion assessed by ELISA and bioassay was increased by EPA at 18 h. Coincubation with anti-TGF-beta antibody inhibited the EPA-induced suppression of [(3)H]-thymidine incorporation and cyclin D1 expression. SB203580, an inhibitor of p38, a downstream kinase of TGF-beta, did not affect EPA's growth inhibitory effect. These results demonstrate that EPA inhibits PDGF-stimulated mesangial cell mitogenesis and cyclin D1 expression via TGF-beta.

20-HETE inhibits the proliferation of vascular smooth muscle cells via transforming growth factor-β

“…Previous studies have indicated that long-chain polyunsaturated fatty acids may modulate cell growth by releasing TGF-b (21). We asked whether 20-HETE inhibited cell proliferation by releasing TGF-b.…”

“…Recent studies indicate that the secretion, activity, and clearance of transforming growth factor-b (TGF-b) can be regulated by long-chain polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) (21,22). EPA inhibits plateletderived growth factor (PDGF)-induced DNA synthesis by stimulating the secretion of TGF-b in mesangial cells (21).…”

“…EPA inhibits plateletderived growth factor (PDGF)-induced DNA synthesis by stimulating the secretion of TGF-b in mesangial cells (21). In addition, fatty acids may attenuate TGF-b clearance and thus increase TGF-b activity (22).…”

“…3E). In addition, 20-HETE may induce vasoconstriction by inhibiting the Ca 21 -activated K 1 channel (8). Nevertheless, pretreatment with paxilline, a K 1 channel inhibitor, did not affect the inhibitory effect of 20-HETE either (Fig.…”

“…20-HETE may act as a potent vasoconstrictor by inhibiting Ca 21 -activated K 1 channels (8) and increasing the conduction of L-type Ca 21 channels (9). In contrast, 20-HETE may be converted by cyclooxygenase to prostaglandins and act as a vasodilator (10)(11)(12).…”