Fan Yang, Li Ya-Ling, Huang Li-Lan, Yang Ji, Hou Yue-Yuan, Bai Yi-Hua
Department of Nephrology, The Second Hospital Affiliated to Kunming Medical University, No.374 Dianmian Road, Wuhua District, KunmingYunnan Province, 650101, China.
Inflammation. 2025 Feb 17. doi: 10.1007/s10753-025-02261-0.
Renal fibrosis and inflammatory infiltration are common pathological features of diabetic kidney disease (DKD). Bone marrow mesenchymal stem cells (BMSCs) are recognized for their anti-fibrotic and anti-inflammatory properties. The objective of this study was to assess the effects of BMSCs on DKD and elucidate their potential mechanisms of action. To assess the role of BMSCs, a DKD model was induced in Sprague-Dawley (SD) rats using streptozotocin (STZ) combined with a high-fat diet, and a human kidney-2 (HK-2) cell damage model was established using high glucose. To investigate the mechanism of the impact of BMSCs on DKD at the genetic level, transcriptome sequencing of the treated HK-2 cells was conducted, identifying the differentially expressed gene SLC3A2, which is related to ferroptosis. A HK-2 cell damage model with SLC3A2 knockout was then constructed to assess the effects of BMSCs on ferroptosis, inflammation, and fibrosis. Also, the potential relationship between BMSCs and the mitogen-activated protein kinase (MAPK) signaling pathway was assessed. In vivo and in vitro studies demonstrated that BMSCs enhanced inflammation and fibrosis in DKD by inhibiting ferroptosis. Knockdown of SLC3A2 promoted ferroptosis, inflammation, and fibrosis, while BMSCs reversed these effects, likely through the inhibition of the MAPK signaling pathway. This research demonstrated that ferroptosis and the activation of the MAPK signaling pathway can promote the onset and progression of DKD. It revealed the therapeutic role of BMSCs in DKD treatment and proposed that SLC3A2 might serve as a potential target for DKD therapy, thereby providing a theoretical foundation for the treatment of DKD.
肾纤维化和炎症浸润是糖尿病肾病（DKD）的常见病理特征。骨髓间充质干细胞（BMSCs）因其抗纤维化和抗炎特性而受到认可。本研究的目的是评估BMSCs对DKD的影响，并阐明其潜在的作用机制。为了评估BMSCs的作用，使用链脲佐菌素（STZ）联合高脂饮食在Sprague-Dawley（SD）大鼠中诱导建立DKD模型，并使用高糖建立人肾-2（HK-2）细胞损伤模型。为了在基因水平上研究BMSCs对DKD影响的机制，对处理后的HK-2细胞进行转录组测序，鉴定出与铁死亡相关的差异表达基因SLC3A2。然后构建SLC3A2敲除的HK-2细胞损伤模型，以评估BMSCs对铁死亡、炎症和纤维化的影响。此外，还评估了BMSCs与丝裂原活化蛋白激酶（MAPK）信号通路之间的潜在关系。体内和体外研究表明，BMSCs通过抑制铁死亡增强了DKD中的炎症和纤维化。敲低SLC3A2可促进铁死亡、炎症和纤维化，而BMSCs可能通过抑制MAPK信号通路逆转了这些作用。本研究表明，铁死亡和MAPK信号通路的激活可促进DKD的发生和发展。它揭示了BMSCs在DKD治疗中的治疗作用，并提出SLC3A2可能作为DKD治疗的潜在靶点，从而为DKD的治疗提供了理论基础。
