Abstract
PGE(2) exerts its biological effect through binding to various EP receptors that result inactivation of various signal transduction pathways. It also plays an important role in mice glomerular mesangial cells (MCs) damage induced by transforming growth factor-β1 (TGF-β1); however, the molecular mechanisms remain unknown. In the present study, we tested the efficacy of four selective agonists of PGE(2) receptor, EP(1)A (17-phenyl trinor prostaglandin E(2) ethyl amid), EP(2)A (butaprost), EP(3)A (sulprostone) and EP(4)A (cay10580), on mice MCs. Compared with the cAMP produced by TGF-β1, additional pretreatment of EP(3)A decreased the cAMP level. MCs treated with EP(1)A and EP(3)A augmented PGE(2), cyclooxygenase-2 (COX-2), membrane-bound PGE synthase 1 (mPGES1), laminin (LN), connective tissue growth factor (CTGF) and cyclin D1 expression stimulated by TGFβ1. EP(1)A and EP(3)A increased the number of cells in S+G2/M phase and reduced cells in G0/G1 phase. EP(1) and EP(3) agonists also strengthened TGFβ1-induced mitogen-activated protein kinase (p38MAPK) and extracellular-signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Whereas MCs treated with EP(2)A and EP(4)A weakened PGE(2), COX-2, mPGES1, LN, CTGF and cyclin D1 expression stimulated by TGFβ1. EP(2)A and EP(4)A decreased the number of cells in S+G2/M phase and increased cells in G0/G1 phase. EP(2) and EP(4) agonists weakened TGFβ1-induced p38MAPK and ERK1/2 phosphorylation. These findings suggest that PGE(2) has an important role in the progression of kidney disease via the EP(1)/EP(3) receptor, whereas EP(2) and EP(4) receptors are equally important in preserving the progression of chronic kidney failure. Thus, agonists of EP(2) and EP(4) receptors may provide a basis for treating kidney damage induced by TGF-β1.