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前列腺素 E 通过 EP2 受体依赖性激活 β-连环蛋白在 5/6 肾切除大鼠中诱导心肌肥厚。

Prostaglandin E induced cardiac hypertrophy through EP2 receptor-dependent activation of β-catenin in 5/6 nephrectomy rats.

机构信息

Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.

Shanghai Medical Center of Kidney, Shanghai, China.

出版信息

ESC Heart Fail. 2021 Jun;8(3):1979-1989. doi: 10.1002/ehf2.13269. Epub 2021 Apr 6.

DOI:10.1002/ehf2.13269
PMID:33822473
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8120373/
Abstract

AIMS

Prostaglandin E (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 RESULTS

We 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.

摘要

目的

前列腺素 E（PGE2）参与了心肌肥厚的发展。然而，PGE2 是否调节慢性肾脏病相关的心肌肥厚以及潜在的机制仍有待阐明。

方法和结果

我们使用定量逆转录聚合酶链反应、western blot、酶联免疫吸附试验、免疫组织化学染色和免疫荧光染色试验，在体外和 5/6 肾切除（5/6NT）大鼠模型中探索了 PGE2 受体抑制剂对心肌肥厚的影响。结果表明，EP2 和 EP4 受体在 PGE2 处理的心肌细胞中均上调。PGE2 处理通过介导 EP2 和 EP4 受体增强活性 β-连环蛋白（非磷酸化）信号。有趣的是，EP2 受体抑制剂抑制了体外 PGE2 诱导的心肌细胞肥大和心肌纤维化相关蛋白。在 5/6NT 大鼠模型中，在 5/6NT 大鼠模型中 2 周时发现 PGE2 分泌增加（P=0.0251）。EP2 受体抑制剂给药显著改善了 5/6NT 大鼠的心脏功能和纤维化。

结论

我们的研究表明，抑制 EP2 受体可以改善 5/6NT 大鼠中 PGE2 诱导的心肌肥厚。对这些机制的探索可能有助于优化伴有心肌肥厚的慢性肾脏病的临床治疗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8dd0/8120373/b4e81297c745/EHF2-8-1979-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8dd0/8120373/e37d468f31f6/EHF2-8-1979-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8dd0/8120373/0e7e11a0c7dc/EHF2-8-1979-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8dd0/8120373/87fc4e2a1edf/EHF2-8-1979-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8dd0/8120373/c4453f16a980/EHF2-8-1979-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8dd0/8120373/90ded5201287/EHF2-8-1979-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8dd0/8120373/02151de8f7cc/EHF2-8-1979-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8dd0/8120373/b4e81297c745/EHF2-8-1979-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8dd0/8120373/e37d468f31f6/EHF2-8-1979-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8dd0/8120373/0e7e11a0c7dc/EHF2-8-1979-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8dd0/8120373/87fc4e2a1edf/EHF2-8-1979-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8dd0/8120373/c4453f16a980/EHF2-8-1979-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8dd0/8120373/90ded5201287/EHF2-8-1979-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8dd0/8120373/02151de8f7cc/EHF2-8-1979-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8dd0/8120373/b4e81297c745/EHF2-8-1979-g007.jpg

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