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Different Effects of EP2 and EP4 Receptors in TGF-β1 Induced Mesangial Cells Injury

Background: The prostaglandin E2 (PGE2) and its receptor subtypes 2 and 4 (EP2 and EP4) in mesangial cells (MCs) proliferation and glomerulosclerosis hasn’t been elaborated in detailed.

Methods: We cultured EP2-/-, EP4flox/flox, and WT mice mesangial cells to detect the relevant indicators and downstream signalling. Additionally, 5/6 nephrectomy were introduced to confirm the in vitro outcomes.

Results: We found that the expression of fibronectin (FN), COX-2 and the phosphorylation level of Smad3 in group EP2-/- obviously increased, with the falling of cyclic adenosine monophosphate (cAMP) level and no protein kinase (PKA) activity. While the relevant genes decreased in EP4 knock out (EP4flox/flox + AD-CRE) group, which represent no significant change in the level of cAMP, although with high level of PKA activity and extracellular signal transduction kinase (ERK) phosphorylation. In vivo study, 24-hour proteinuria, serum creatinine and urea nitrogen in EP4+/- group obviously declined, and the degree of glomerular sclerosis and the density of FN and COX-2 in glomerulus reduced significantly. EP2-/- show a totally opposite event to EP4+/- .

Conclusion: EP2 receptor mainly depends on cAMP/PKA to inhibit effect of PGE2 induced by TGF-β1/Smad3 pathway and further alleviate the damage of MCs. While EP4 may coordinate the effect of MCs injury through ERK phosphorylation. Our finding suggests the pleiotropic functions of PGE2, and thus explores a potential therapy on the level of gene mediation.


Xiaolan Chen, Jing Wang, Hu Xu, Tianyi Pan, Yuying Xu, Xu Chen, Yaping Fan

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