Abstract
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.
Highlights
Renal fibrosis, the main cause to CKD, play a pivotal role in the progression of ERSD
With the presence of 10 ng/ml TGF-β1 on mesangial cells (MCs) for 5 min and 12 h respectively, secretion of prostaglandin E2 (PGE2) could facilitate, and the change in latter time point was of statistical significance (p
Each group were stimulated by TGF-β1 with 10 ng/ml for 5 min to strengthen the average level of the phosphorylation of the signaling (p
Summary
The main cause to CKD (chronic kidney disease), play a pivotal role in the progression of ERSD (end renal stage disease). The quantities of EP2 in glomerulus are relatively small, it was reported that after mice were subjected to subtotal nephrectomy, the manifestation of EP2 receptor obviously increased [11]. Results: We found that the expression of fibronectin (FN), COX-2 and the phosphorylation level of Smad in group EP2-/- obviously increased, with the falling of cyclic adenosine monophosphate (cAMP) level and no protein kinase (PKA) activity [2]. While the relevant genes decreased in EP4 knock out (EP4flox/flox + AD-CRE) group, which represent no significant change in the level of cAMP, with high level of PKA activity and extracellular signal transduction kinase (ERK) phosphorylation. Conclusion: EP2 receptor mainly depends on cAMP/PKA to inhibit effect of PGE2 induced by TGF-β1/Smad pathway and further alleviate the damage of MCs [4]. Our finding suggests the pleiotropic functions of PGE2, and explores a potential therapy on the level of gene mediation [5]
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