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(American Journal of Pathology. 2004;164:937-946.)
© 2004 American Society for Investigative Pathology

Lipoxins Inhibit Akt/PKB Activation and Cell Cycle Progression in Human Mesangial Cells

Derick Mitchell*{dagger}§, Karen Rodgers*{dagger}§, Jennifer Hanly*{dagger}§, Blaithin McMahon*{dagger}§, Hugh R. Brady*{dagger}§, Finian Martin{dagger}{ddagger}§ and Catherine Godson*{dagger}§

From the Center for Molecular Inflammation and Vascular Research, *Department of Medicine and Therapeutics, Mater Misericordiae Hospital, Dublin; The Conway Institute of Biomolecular and Biomedical Research {dagger}, Dublin; the Department of Pharmacology, {ddagger}University College Dublin, Belfield, Dublin; and The Dublin Molecular Medicine Centre, §Dublin, Ireland

Lipoxins (LX) are endogenously produced eicosanoids with a spectrum of bioactions that suggest anti-inflammatory, pro-resolution roles for these agents. Mesangial cell (MC) proliferation plays a pivotal role in the pathophysiology of glomerular inflammation and is coupled to sclerosis and tubulointerstitial fibrosis. We have previously reported that LXA4 acts through a specific G-protein-coupled-receptor (GPCR) to modulate MC proliferation in response to the proinflammatory mediators LTD4 and platelet-derived growth factor (PDGF). Further investigations revealed that these effects were mediated by modulation of receptor tyrosine kinase activity. Here we have explored the underlying mechanisms and report inhibition of growth factor (PDGF; epithelial growth factor) activation of Akt/PKB by LXA4. LXA4 (10 nmol/L) modulates PDGF-induced (10 ng/ml, 24 hours) decrements in the levels of cyclin kinase inhibitors p21Cip1 and p27Kip1. PDGF-induced increases in CDK2-cyclin E complex formation are also inhibited by LXA4. The potential of LXA4 as an anti-inflammatory therapeutic is compromised by its degradation; this has been circumvented by synthesis of stable analogs. We report that 15-(R/S)-methyl-LXA4 and 16-phenoxy-LXA4 mimic the native compound with respect to modulation of cell proliferation and PDGF-induced changes in cell cycle proteins. In vivo, MC proliferation in response to PDGF is associated with TGFß1 production and the subsequent development of renal fibrosis. Here we demonstrate that prolonged (24 to 48 hours) exposure to PDGF is associated with autocrine TGFß1 production, which is significantly reduced by LXA4. In aggregate these data demonstrate that LX inhibit PDGF stimulated proliferation via modulation of the PI-3-kinase pathway preventing mitogen-elicited G1-S phase progression and suggest the therapeutic potential of LX as anti-fibrotic agents.




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