Pei Xiaoyan, Liu Jie, Wei Yu, Zhu Yanhui, Li Yu, Wang Qiong, Zhuang Langen, Jin Guoxi
Department of Endocrinology, the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, PR China.
Department of Endocrinology, the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, PR China.
Int Immunopharmacol. 2025 Jun 5;157:114786. doi: 10.1016/j.intimp.2025.114786. Epub 2025 May 3.
Diabetic kidney disease (DKD) is widely recognized as a prevalent and major microvascular complication of diabetes mellitus. Mitofusin 2 (MFN2) has been closely linked to the development of diabetes mellitus, yet its precise role in the pathogenesis of DKD remains uncertain. The objective of our current research was to explore the role of MFN2 in the advanced DKD and its underlying molecular pathway. This research was to examine the involvement and molecular pathways of MFN2 in the advancement of DKD.
In this study, MFN2 was manipulated in high glucose (HG)-treated HK2 cells to investigate its impact on cell proliferation, apoptosis, and mitochondrial oxidative phosphorylation. Models of MFN2 overexpression or silencing were established in db/db mice as a diabetes model. The alterations in kidney morphology, renal fibrosis severity, macrophage polarization, and related inflammatory factors (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], and interleukin-1β [IL-1β]) were evaluated. Furthermore, HK2 cells were co-cultivated with M1-type macrophages to examine the impact of MFN2 expression on macrophage polarization. Subsequently, we delved deeper into the upstream mechanisms utilizing the STRING database.
Our study identified that MFN2 expression was downregulated in HG-treated HK-2 cells. The overexpression of MFN2 resulted in increased HK2 cell proliferation, improved degree of oxidative phosphorylation, and reduced apoptosis. In db/db mice, MFN2 overexpression exerted a protective effect on DKD-induced nephropathy and fibrosis. Notably, MFN2 overexpression influenced macrophage polarization and modulated expression of related inflammatory factors by promoting mitochondrial oxidative phosphorylation. Additionally, STRING database prediction revealed that PTEN-induced kinase 1 (PINK1) regulated MFN2 expression, which was consistent with MFN2 changes in DKD, and this regulation was associated with DKD progression.
The role of MFN2 in maintaining mitochondrial function in DKD may be regulated by PINK1 and provides a new potential therapeutic target for DKD.
糖尿病肾病（DKD）是糖尿病常见且主要的微血管并发症。线粒体融合蛋白2（MFN2）与糖尿病的发生发展密切相关，但其在DKD发病机制中的具体作用仍不明确。我们当前研究的目的是探讨MFN2在晚期DKD中的作用及其潜在分子途径。本研究旨在检测MFN2在DKD进展中的参与情况及分子途径。
在本研究中，对高糖（HG）处理的HK2细胞进行MFN2调控，以研究其对细胞增殖、凋亡和线粒体氧化磷酸化的影响。在作为糖尿病模型的db/db小鼠中建立MFN2过表达或沉默模型。评估肾脏形态改变、肾纤维化严重程度、巨噬细胞极化及相关炎症因子（肿瘤坏死因子-α [TNF-α]、白细胞介素-6 [IL-6]和白细胞介素-1β [IL-1β]）的变化。此外，将HK2细胞与M1型巨噬细胞共培养，以检测MFN2表达对巨噬细胞极化的影响。随后，利用STRING数据库深入研究上游机制。
我们的研究发现，HG处理的HK-2细胞中MFN2表达下调。MFN2过表达导致HK2细胞增殖增加、氧化磷酸化程度改善及凋亡减少。在db/db小鼠中，MFN2过表达对DKD诱导的肾病和纤维化具有保护作用。值得注意的是，MFN2过表达通过促进线粒体氧化磷酸化影响巨噬细胞极化并调节相关炎症因子的表达。此外，STRING数据库预测显示，PTEN诱导激酶1（PINK1）调节MFN2表达，这与DKD中MFN2的变化一致，且这种调节与DKD进展相关。
MFN2在DKD中维持线粒体功能的作用可能受PINK1调节，为DKD提供了一个新的潜在治疗靶点。
