Apelin 的反应性升高可抑制慢性间歇性低氧诱导的肾纤维化。

Elevated reactivity of Apelin inhibited renal fibrosis induced by chronic intermittent hypoxia.

机构信息

Key Laboratory of Applied Pharmacology in Universities of Shandong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang, 261053, Shandong, China.

出版信息

Arch Biochem Biophys. 2021 Oct 30;711:109021. doi: 10.1016/j.abb.2021.109021. Epub 2021 Aug 28.

DOI:10.1016/j.abb.2021.109021

PMID:34464591

Abstract

BACKGROUND

Apelin and its receptor angiotensin receptor - like 1 (APJ) are closely related to renal fibrosis, but their specific roles in renal fibrosis are still controversial. In this article, we discussed the role of Apelin/APJ system in renal fibrosis and its mechanism.

METHODS

Chronic intermittent hypoxia (CIH) rat model was established to induce the environment of renal fibrosis and a competitive antagonist of the APJ receptor ML221 was administered to CIH rats. The rats were divided into Control, CIH and ML221 groups. HE staining was used to detect the inflammatory injury and fibrosis of renal tissue. The expressions of renal fibrosis-related indicators transforming growth factor-β (TGF-β), α-smooth muscle actin (α-SMA) and Human type I collagen (Col-Ⅰ) were detected by immunohistochemistry. The levels of oxidative stress indexes reactive oxygen species (ROS), Malondialdehyde (MDA), Superoxide Dismutase (SOD) and inflammation-related indexes Interleukin (IL) -6, tumor necrosis factor-α (TNF-α) and IL-1β were detected by ELISA. At the same time, the levels of Apelin-13 and AngiotensinII (AngⅡ) were also measured by ELISA. Finally, western blot was used to detect the expression of Apelin pathway and renal fibrosis-related proteins. In addition, at the cellular level, we divided the cells into Control, CIH, Apelin-13 and Apelin-13+ML-221 groups to further verify the specific mechanisms at the cellular level.

RESULTS

The expression of Apeline-13 and its related pathways was significantly increased after the induction of CIH in rats. However, the degree of renal fibrosis in ML221 group was further significantly increased after inhibiting the expression of Apelin. At the cellular level, CIH model cells treated with Apelin-13 significantly reduced cell proliferation, oxidative stress and inflammatory response, and decreased the expression of fibrosis-related proteins, which can be reversed by ML221 administration.

CONCLUSION

The increased reactivity of Apelin may be one of the protective mechanisms against renal fibrosis induced by CIH.

摘要

背景

Apelin 和其受体血管紧张素受体样 1（APJ）与肾纤维化密切相关，但它们在肾纤维化中的具体作用仍存在争议。本文探讨了 Apelin/APJ 系统在肾纤维化中的作用及其机制。

方法

建立慢性间歇性低氧（CIH）大鼠模型诱导肾纤维化环境，并给予 APJ 受体竞争性拮抗剂 ML221。将大鼠分为对照组、CIH 组和 ML221 组。HE 染色检测肾组织的炎症损伤和纤维化程度。免疫组化检测肾纤维化相关指标转化生长因子-β（TGF-β）、α-平滑肌肌动蛋白（α-SMA）和人 I 型胶原（Col-Ⅰ）的表达。ELISA 法检测氧化应激指标活性氧（ROS）、丙二醛（MDA）、超氧化物歧化酶（SOD）和炎症相关指标白细胞介素（IL）-6、肿瘤坏死因子-α（TNF-α）和 IL-1β的水平。同时，ELISA 法检测 Apelin-13 和血管紧张素Ⅱ（AngⅡ）的水平。最后，western blot 法检测 Apelin 通路及肾纤维化相关蛋白的表达。此外，在细胞水平上，我们将细胞分为对照组、CIH 组、Apelin-13 组和 Apelin-13+ML-221 组，进一步验证细胞水平的具体机制。

结果

CIH 诱导大鼠后，Apeline-13 及其相关通路的表达明显增加。然而，抑制 Apelin 表达后，ML221 组的肾纤维化程度进一步显著增加。在细胞水平上，用 Apelin-13 处理 CIH 模型细胞后，细胞增殖、氧化应激和炎症反应明显减少，纤维化相关蛋白表达减少，给予 ML221 后可逆转上述作用。