15-Deoxy-Δ12,14-prostaglandin J2 regulates mesangial cell proliferation and death

Abstract

Proliferation of intrinsic glomerular cells is a common response to renal injury. Acutely, proliferation may be beneficial, but sustained glomerular hypercellularity after injury is associated with progressive renal failure. To identify endogenous factors that may be responsible for regulating glomerular cell number, the effects of J-series cyclopentenone prostaglandins (PGs) on human glomerular mesangial cell proliferation and death were examined. Human mesangial cells were grown in the presence or absence of PGJ2 or its metabolite 15-Deoxy-Delta12,14-PGJ2 (15dPGJ2). The number of viable cells was measured by the reduction of the tetrazolium MTS to a colored formazan product. Apoptosis was assessed by caspase-3 activation and DNA fragmentation. PGJ2 at concentrations up to 10 micromol/L caused mesangial proliferation. 15dPGJ2 also caused mesangial proliferation at low concentrations (< or =2.5 micromol/L), but induced mesangial cell death at higher concentrations (>5 micromol/L). Cell death occurred in part through apoptosis, measured as an increase in caspase-3 activity and DNA fragmentation in 15dPGJ2-treated cells. Cell death was associated with a decline in baseline phosphorylation of the survival factor Akt and increased Akt degradation, whereas 15dPGJ2-induced mesangial proliferation was blocked by inhibition of the PI 3-kinase/Akt pathway. 15dPGJ2 is a potent PPARgamma agonist. Like 15dPGJ2, treatment of mesangial cells with thiazolidinedione-type PPARgamma ligands (10 to 20 micromol/L) caused significant cell death, but at lower concentrations also caused a small degree of proliferation. J-series prostaglandins thus may be involved in the initiation of glomerular hypercellularity through Akt-dependent proliferation, and restoration of normal glomerular architecture through PPARgamma-mediated apoptosis. Manipulation of these prostaglandins may be relevant to the treatment of progressive glomerular disease.