Prostaglandin E₂ induced cardiac hypertrophy through EP2 receptor‐dependent activation of β‐catenin in 5/6 nephrectomy rats

Abstract

Aims Prostaglandin E 2 (PGE2) is involved in the development of cardiac hypertrophy. However, whether PGE2 regulates the chronic kidney disease-associated cardiac hypertrophy and the tentative mechanism remains to be elucidated. Methods and resultsWe explored the effect of PGE2 receptor inhibitors on cardiac hypertrophy in vitro and in a 5/6 nephrectomy (5/6NT) rat model using quantitative reverse transcription polymerase chain reaction, western blotting, enzyme-linked immunosorbent assay, immunohistochemical staining, and immunofluorescence staining assays. The result showed that EP2 and EP4 receptors were both up-regulated in the PGE2-treated cardiomyocyte cells. PGE2 treatment enhanced active β-catenin (non-phosphorylated) signalling through mediating EP2 and EP4 receptors. Interestingly, inhibition of EP2 receptor suppressed PGE2-induced cardiomyocyte hypertrophy and cardiac fibrosis-related proteins in vitro. In the 5/6NT rat model, the increased secretion PGE2 was identified in the 5/6NT rat model for 2 weeks (P = 0.0251). EP2 receptor inhibitor administration significantly improved the cardiac function and fibrosis in 5/6NT rats. Conclusions Our study demonstrated that inhibition of EP2 receptor could improve PGE2-induced cardiac hypertrophy in 5/6NT rats. The exploration of these mechanisms may contribute to the optimization of therapy in chronic kidney disease accompanied cardiac hypertrophy in clinic.

The Link between Prostanoids and Cardiovascular Diseases

“…The binding of EP1 receptors to cardiac fibroblasts seems to increase their proliferation and collagen deposition, worsening cardiac recovery after ischemia [ 203 ]. Instead, EP2 receptors appear to induce cardiac hypertrophy after the interaction with PGE2 in cardiomyocytes [ 204 ].…”

Dedifferentiation of Human Cardiac Myofibroblasts Is Independent of Activation of COX-2/PGE2 Pathway

“…PGE 2 increases expression of both EP2 and EP4 receptors. EP2 receptor activation enhances expression of TGF-β1, collagen I and III in H9C2 cardiac myocytes [ 21 ]. PGE 2 is the direct enzymatic product of COX-2.…”

“…In contrary to inhibition of lung fibroblast proliferation, PGE 2 stimulates cardiac fibroblast proliferation and p42/44 MAPK pathway [ 32 ]. PGE 2 up-regulates expression of EP2 and EP4 as well as levels of fibrosis-associated protein expression such as TGF-β1, collagen I and III in H9C2 cardiac myocytes [ 21 ]. Selective antagonism of EP2 receptor with AH6809 blocks increased expression of TGF-β1, collagen I and III in both cardiac myocytes and a chronic kidney disease-associated cardiac hypertrophy and fibrosis [ 20 ].…”

Drug repurposing screens to identify potential drugs for chronic kidney disease by targeting prostaglandin E2 receptor

“…In other cases, PGE2-EP2/EP4 signaling mediates the expression of anti-inflammatory cytokines through anti-inflammatory cytokine IL-10 signaling and function [41] . The inhibition of cytokine TGF-β-induced cell proliferation in vivo is directly inhibited by PGE2 through EP2 and EP4 [42] , which might be involved in the PKC–Raf1–MEK1/2–ERK1/2, PKA/AKT, and MAPK/ERK signaling pathways in the prevention of the progression of CKD [43] . In our present study, the normalized NGS gene expression data successfully identified a significant PTGER2 gene, the EP2 protein, that is activated in response to human kidney cells after treatment with an ECE inhibitor by using IPA database analysis.…”