Inhibition of SGLT2 protects podocytes in diabetic kidney disease by rebalancing mitochondria-associated endoplasmic reticulum membranes.

IF 8.2 2区生物学 Q1 CELL BIOLOGY

Cell Communication and Signaling Pub Date : 2024-11-07 DOI:10.1186/s12964-024-01914-1

Xuehong Li, Qiong Li, Xinying Jiang, Shicong Song, Wei Zou, Qinglan Yang, Sirui Liu, Shuangqin Chen, Cheng Wang

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引用次数: 0

Abstract

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have changed the therapeutic landscape for diabetic kidney disease (DKD) patients, but their underlying mechanisms are complicated and not fully understood. Mitochondria-associated endoplasmic reticulum membranes (MAMs), the dynamic contact sites between mitochondria and the endoplasmic reticulum (ER), serve as intracellular platforms important for regulating cellular fate and function. This study explored the roles and mechanisms of SGLT2 inhibitors in regulating MAMs formation in diabetic podocytes.

Methods: We assessed MAMs formation in podocytes from DKD patients' renal biopsy samples and induced an increase in MAMs formation in cultured human podocytes by transfecting OMM-ER linker plasmid to investigate the effects of MAMs imbalance on podocyte injury. Empagliflozin-treated diabetic mice and podocyte-specific SGLT2 knockout diabetic mice (diabetic states were induced by streptozotocin and a high-fat diet), empagliflozin-treated podocytes, SGLT2-downregulated podocytes, and SGLT2-overexpressing podocytes were used to investigate the effects and mechanisms of SGLT2 inhibitors on MAMs formation in diabetic podocytes.

Results: MAMs were increased in podocytes and were associated with renal dysfunction in DKD patients. Increased MAMs aggravated HG-induced podocyte injury. The expression of SGLT2 was increased in diabetic podocytes. In addition, empagliflozin-treatment and podocyte-specific SGLT2 knockout attenuated MAMs formation and podocyte injury in diabetic mice. Empagliflozin treatment and SGLT2 knockdown decreased podocyte MAMs formation by activating the AMP-activated protein kinase (AMPK) pathway, while SGLT2 overexpression had the opposite effect.

Conclusions: Inhibition of SGLT2 attenuates MAMs imbalance in diabetic podocytes by activating the AMPK pathway. This study expands our knowledge of the roles of SGLT2 inhibitors in improving DKD podocyte injury and provides new insights into DKD treatment.

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通过重新平衡线粒体相关内质网膜，抑制 SGLT2 可保护糖尿病肾病患者的荚膜细胞。

背景：钠-葡萄糖共转运体2（SGLT2）抑制剂改变了糖尿病肾病（DKD）患者的治疗格局，但其潜在机制却十分复杂，尚未完全明了。线粒体相关内质网膜（MAMs）是线粒体和内质网（ER）之间的动态接触点，是调节细胞命运和功能的重要细胞内平台。本研究探讨了 SGLT2 抑制剂在调节糖尿病荚膜细胞 MAMs 形成中的作用和机制：我们评估了来自 DKD 患者肾活检样本的荚膜细胞中 MAMs 的形成，并通过转染 OMM-ER 连接质粒诱导培养的人荚膜细胞中 MAMs 形成的增加，以研究 MAMs 失衡对荚膜细胞损伤的影响。利用恩格列净处理的糖尿病小鼠和荚膜特异性SGLT2基因敲除糖尿病小鼠（通过链脲佐菌素和高脂饮食诱导糖尿病状态）、恩格列净处理的荚膜、SGLT2下调的荚膜和SGLT2表达的荚膜，研究SGLT2抑制剂对糖尿病荚膜MAMs形成的影响和机制：结果：MAMs在荚膜细胞中增加，并与DKD患者的肾功能障碍有关。MAMs 的增加加重了 HG 诱导的荚膜损伤。糖尿病荚膜细胞中 SGLT2 的表达增加。此外，恩格列净治疗和荚膜特异性 SGLT2 基因敲除可减轻糖尿病小鼠 MAMs 的形成和荚膜损伤。Empagliflozin 治疗和 SGLT2 基因敲除通过激活 AMP 激活蛋白激酶（AMPK）通路减少了荚膜 MAMs 的形成，而 SGLT2 基因过表达则产生了相反的效果：结论：通过激活 AMPK 通路，抑制 SGLT2 可减轻糖尿病荚膜细胞中 MAMs 的失衡。这项研究拓展了我们对 SGLT2 抑制剂在改善糖尿病荚膜细胞损伤中的作用的认识，并为糖尿病荚膜细胞损伤的治疗提供了新的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Communication and Signaling CELL BIOLOGY-

CiteScore

11.00

自引率

0.00%

发文量

180

期刊介绍： Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.