Effect of selective inhibition or activation of PGE2 EP1 receptor on glomerulosclerosis.

Prostaglandin E2 (PGE2) is involved in numerous physiological and pathological processes of the kidney via its four receptors. A previous study has suggested that a defect in the PGE2 receptor 1 (EP1) gene markedly suppressed the transforming growth factor-beta 1 (TGF-beta 1)-induced mesangial cell (MC) proliferation and extracellular matrix aggregation. Therefore, the present study aimed to adopt a pharmacological method of specifically suppressing or activating the EP1 receptor to further verify and demonstrate these results. The EP1 receptor antagonist SC-19220 and EP1 receptor agonist 17-phenyl-trinor-PGE2 ethyl amide (17-pt-PGE2) were selectively used to treat five-sixths nephrectomy renal fibrosis model mice and TGF-beta 1-stimulated MCs. An Alpha screen PGE2 assay kit, flow cytometry, western blotting and immunohistochemical techniques were adopted to perform in vivo and in vitro experiments. The present results suggested that compared with the control group, the selective EP1 receptor antagonist SC-19220 improved renal function, markedly reduced the plasma blood urea nitrogen and creatinine levels (P<0.05) and alleviated glomerulosclerosis (P<0.05). By contrast, the EP1 receptor agonist 17-pt-PGE2 aggravated renal dysfunction and glomerulosclerosis (P<0.05). To verify the renal protection mechanisms mediated by suppression of the EP1 receptor, the expression levels of endoplasmic reticulum stress (ERS)-related proteins, including chaperone glucose-regulated protein 78 (GRP78), transient receptor potential channel 1 (TRPC1) and protein kinase R-like endoplasmic reticulum kinase (PERK), were further evaluated histologically. The expression of GRP78, TRPC1 and PERK in the antagonist treatment group were markedly downregulated (P<0.05), whereas those in the agonist treatment group were upregulated (P<0.05). The present in vitro experiments demonstrated that, compared with the control group, the EP1 receptor antagonist suppressed the expression of GRP78, TRPC1 and PERK (P<0.05), reduced the production of PGE2 (P<0.05) and decreased the MC apoptosis rate (P<0.05), thus alleviating TGF-beta 1-stimulated MC injury. Consequently, consistent with previous results, selectively antagonizing the EP1 receptor improved renal function and mitigated glomerulosclerosis, and its potential mechanism might be associated with the suppression of ERS.