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

Background. 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. Methods. Human mesangial cells were grown in the presence or absence of PGJ(2) or its metabolite 15-Deoxy Delta(12,14)-PGJ(2) (15dPGJ(2)). 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. Results. PGJ(2) at concentrations up to 10 mumol/L caused mesangial proliferation. 15dPGJ(2) also caused mesangial proliferation at low concentrations (less than or equal to2.5 mumol/L), but induced mesangial cell death at higher concentrations (>5 mumol/L). Cell death occurred in part through apoptosis, measured as an increase in caspase-3 activity and DNA fragmentation in 15dPGJ(2)-treated cells. Cell death was associated with a decline in baseline phosphorylation of the survival factor Akt and increased Akt degradation, whereas 15dPGJ(2)-induced mesangial proliferation was blocked by inhibition of the PI3-kinase/Akt pathway. 15dPGJ(2) is a potent PPARgamma agonist. Like 15dPGJ(2), treatment of mesangial cells with thiazolidinedione-type PPARgamma ligands (10 to 20 mumol/L) caused significant cell death, but at lower concentrations also caused a small degree of proliferation. Conclusions. 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.