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

Chen,Xu; Yin,Jun; Xu,Yuyin; Qiu,Zhi; Liu,Jing; Chen,Xiaolan

doi:10.3892/mmr.2020.11353

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

Authors:
- Xu Chen
- Jun Yin
- Yuyin Xu
- Zhi Qiu
- Jing Liu
- Xiaolan Chen
View Affiliations

Affiliations: Department of Nephrology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China, Department of Nephrology, Wuxi No. 2 People's Hospital, Wuxi, Jiangsu 214000, P.R. China, Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
Published online on: July 23, 2020 https://doi.org/10.3892/mmr.2020.11353
Pages: 2887-2895
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

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‑β1 (TGF‑β1)‑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‑β1‑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‑β1‑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.

View Figures

View References

1	Humphreys BD: Mechanisms of renal fibrosis. Annu Rev Physiol. 10:2887–326. 2018.
2	Nogueira A, Pires MJ and Oliveira PA: Pathophysiological mechanisms of renal fibrosis: A review of animal models and therapeutic strategies. In Vivo. 31:1–22. 2017. View Article : Google Scholar : PubMed/NCBI
3	Meng XM, Zhang Y, Huang XR, Ren GL, Li J and Lan HY: Treatment of renal fibrosis by rebalancing TGF-β/Smad signaling with the combination of asiatic acid and naringenin. Oncotarget. 6:36984–36997. 2015. View Article : Google Scholar : PubMed/NCBI
4	Loboda A, Sobczak M, Jozkowicz A and Dulak J: TGF-β1/Smads and miR-21 in renal fibrosis and inflammation. Mediators Inflamm. 2016:83192832016. View Article : Google Scholar : PubMed/NCBI
5	Chen X, Jiang D, Wang J, Chen X, Xu X, Xi P, Fan Y, Zhang X and Guan Y: Prostaglandin E2 EP1 receptor enhances TGF-β1-induced mesangial cell injury. Int J Mol Med. 35:285–293. 2015. View Article : Google Scholar : PubMed/NCBI
6	Nasrallah R, Hassouneh R and Hébert RL: Chronic kidney disease: Targeting prostaglandin E2 receptors. Am J Physiol Renal Physiol. 307:F243–F250. 2014. View Article : Google Scholar : PubMed/NCBI
7	Akaba T, Komiya K, Suzaki I, Kozaki Y, Tamaoki J and Rubin BK: Activating prostaglandin E2 receptor subtype EP4 increases secreted mucin from airway goblet cells. Pulm Pharmacol Ther. 48:117–123. 2018. View Article : Google Scholar : PubMed/NCBI
8	Jin Y, Smith C, Hu L, Coutant DE, Whitehurst K, Phipps K, McNearney TA, Yang X, Ackermann B, Pottanat T and Landschulz W: LY3127760, a selective prostaglandin E4 (EP4) receptor antagonist and celecoxib: A comparison of pharmacological profles. Clin Transl Sci. 11:46–53. 2018. View Article : Google Scholar : PubMed/NCBI
9	Fujioka H, Funabashi T and Akema T: Prostaglandin E2 modulates presynaptic regulation of GnRH neurons via EP4 receptors in accordance with estrogen milieu. Neuroscience. 30:139–145. 2017. View Article : Google Scholar
10	Thieme K, Majumder S, Brijmohan AS, Batchu SN, Bowskill BB, Alghamdi TA, Advani SL, Kabir MG, Liu Y and Advani A: EP4 inhibition attenuates the development of diabetic and non-diabetic experimental kidney disease. Sci Rep. 7:34422017. View Article : Google Scholar : PubMed/NCBI
11	Hong YA, Yang KJ, Jung SY, Park KC, Choi H, Oh JM, Lee SJ, Chang YK, Park CW, Yang CW, et al: Paricalcitol pretreatment attenuates renal ischemia-reperfusion injury via prostaglandin E2 receptor EP4 pathway. Oxid Med Cell Longev. 2017:50319262017. View Article : Google Scholar : PubMed/NCBI
12	Jiang J, Qiu J, Li Q and Shi Z: Prostaglandin E2 signaling: Alternative target for glioblastoma? Trends Cancer. 3:75–78. 2017. View Article : Google Scholar : PubMed/NCBI
13	Bai X, Wang J, Guo Y, Pan J, Yang Q, Zhang M, Li H, Zhang L, Ma J, Shi F, et al: Prostaglandin E2 stimulates β1-integrin expression in hepatocellular carcinoma through the EP1 receptor/PKC/NF-κB pathway. Sci Rep. 4:65382014. View Article : Google Scholar : PubMed/NCBI
14	Cybulsky AV: Endoplasmic reticulum stress, the unfolded protein response and autophagy in kidney diseases. Nat Rev Nephrol. 13:681–696. 2017. View Article : Google Scholar : PubMed/NCBI
15	Inagi R: Endoplasmic reticulum stress as a progression factor for kidney injury. Curr Opin Pharmacol. 10:156–165. 2010. View Article : Google Scholar : PubMed/NCBI
16	Sours-Brothers S, Ding M, Graham S and Ma R: Interaction between TRPC1/TRPC4 assembly and STIM1 contributes to store-operated Ca2+ entry in mesangial cells. Exp Biol Med (Maywood). 234:673–682. 2009. View Article : Google Scholar : PubMed/NCBI
17	Vetterkind S, Poythress RH, Lin QQ and Morgan KG: Hierarchical scaffolding of an ERK1/2 activation pathway. Cell Commun Signal. 11:652013. View Article : Google Scholar : PubMed/NCBI
18	Guan Y, Zhang Y, Wu J, Qi Z, Yang G, Dou D, Gao Y, Chen L, Zhang X, Davis LS, et al: Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting. J Clin Invest. 117:2496–2505. 2007. View Article : Google Scholar : PubMed/NCBI
19	Makino H, Tanaka I, Mukoyama M, Sugawara A, Mori K, Muro S, Suganami T, Yahata K, Ishibashi R, Ohuchida S, et al: Prevention of diabetic nephropathy in rats by prostaglandin E receptor EP1-selective antagonist. J Am Soc Nephrol. 13:1757–1765. 2002. View Article : Google Scholar : PubMed/NCBI
20	González AA, Céspedes C, Villanueva S, Michea L and Vio CP: E Prostanoid-1 receptor regulates renal medullary alphaENaC in rats infused with angiotensin II. Biochem Biophys Res Commun. 389:372–327. 2009. View Article : Google Scholar : PubMed/NCBI
21	Xu Y, Wang J, Pan T, Chen X, Xu X, Jiang D and Yin J: Role of the ER stress in prostaglandin E2/E-prostanoid 2 receptor involved TGF-β1-induced mice mesangial cell injury. Mol Cell Biochem. 411:43–55. 2016. View Article : Google Scholar : PubMed/NCBI
22	Santangelo S, Shoup M, Gamelli RL and Shankar R: Prostaglandin E2 receptor antagonist (SC-19220) treatment restores the balance to bone marrow myelopoiesis after burn sepsis. J Trauma. 48:826–830. 2000. View Article : Google Scholar : PubMed/NCBI
23	Yang GX, Xu YY, Fan YP, Wang J, Chen X, Zhang Y and Wu J: A maladaptive role for EP4 receptors in mouse mesangial cells. PLoS One. 9:e1040912014. View Article : Google Scholar : PubMed/NCBI
24	Das F, Ghosh-Choudhury N, Kasinath BS and Choudhury GG: TGFβ enforces activation of eukaryotic elongation factor-2 (eEF2) via inactivation of eEF2 kinase by p90 ribosomal S6 kinase (p90Rsk) to induce mesangial cell hypertrophy. FEBS Lett. 584:4268–4272. 2010. View Article : Google Scholar : PubMed/NCBI
25	Cao Y, Pan T, Chen X, Wu J, Guo N and Wang B: EP4 knockdown alleviates glomerulosclerosis through Smad and MAPK pathways in mesangial cells. Mol Med Rep. 18:5141–5150. 2018.PubMed/NCBI
26	Liu S, Ji Y, Yao J, Zhao X, Xu H, Guan Y, Breyer RM, Sheng H and Zhu J: Knockout of the prostaglandin E2 receptor subtype 3 promotes eccentric cardiac hypertrophy and fibrosis in mice. J Cardiovasc Pharmacol Ther. 22:71–82. 2017. View Article : Google Scholar : PubMed/NCBI
27	Gao Y, Zhao C, Wang W, Jin R, Li Q, Ge Q, Guan Y and Zhang Y: Prostaglandins E2 signal mediated by receptor subtype EP2 promotes IgE production in vivo and contributes to asthma development. Sci Rep. 6:205052016. View Article : Google Scholar : PubMed/NCBI
28	Xu H, Du S, Fang B, Li C, Jia X, Zheng S, Wang S, Li Q, Su W, Wang N, et al: VSMC-specific EP4 deletion exacerbates angiotensin II-induced aortic dissection by increasing vascular inflammation and blood pressure. Proc Natl Acad Sci USA. 116:8457–8462. 2019. View Article : Google Scholar : PubMed/NCBI
29	Zhang D, Yang H, Kong X, Wang K, Mao X, Yan X, Wang Y, Liu S, Zhang X, Li J, et al: Proteomics analysis reveals diabetic kidney as a ketogenic organ in type 2 diabetes. Am J Physiol Endocrinol Metab. 300:E287–E295. 2011. View Article : Google Scholar : PubMed/NCBI
30	Gombedza FC, Shin S, Kanaras YL and Bandyopadhyay BC: Abrogation of store-operated Ca²⁺ entry protects against crystal-induced ER stress in human proximal tubular cells. Cell Death Discov. 5:1242019. View Article : Google Scholar : PubMed/NCBI