Shi Jianmei, Wang Yuxiang, Liang Tao, Wang Xixi, Xie Jingxiao, Huang Renbin, Xu Xiaohui, Wei Xiaojie
Department of Physiology, College of Basic Medicine, Guangxi University of Chinese Medicine, Nanning, 530021, Guangxi, China.
Guangxi Key Laboratory of Translational Medicine for Treating High-Incidence Infectious Diseases with Integrative Medicine, Nanning, 530021, Guangxi, China.
Chin Med. 2024 Sep 12;19(1):125. doi: 10.1186/s13020-024-00993-z.
Studies have shown that Averrhoa carambola L. possesses therapeutic potential for diabetes and related complications. However, the specific beneficial effects and molecular mechanisms of 2-dodecyl-6-meth-oxycyclohexa-2,5-diene-1,4-dione (DMDD) isolated from Averrhoa carambola L. on diabetic nephropathy (DN) require further investigation.
80 C57BL/6 J male mice were subjected to a 1-week adaptive feeding, followed by a high-fat diet and intraperitoneal injection of 100 mg/kg streptozotocin (STZ) to construct an in vivo DN model. Additionally, human renal proximal tubular epithelial cells (HK-2) induced by high glucose (HG) were used as an in vitro DN model. The expression levels of epithelial-mesenchymal transition (EMT), endoplasmic reticulum stress (ERS), and autophagy-related proteins in renal tubular cells were detected by Western Blot, flow cytometry, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA) staining. Transcriptome analysis revealed was conducted to elucidate the specific mechanism of by which DMDD mitigates DN by inhibiting ERS and autophagy. HK-2 cells were transfected with IRE1α overexpression lentivirus to reveal the role of IRE1α overexpression in HG-induced HK-2.
The experimental data showed that DMDD significantly reduced blood glucose levels and improved renal pathological alterations in DN mice. Additionally, DMDD inhibited the calcium (Ca) pathway, manifested by decreased autophagosome formation and downregulation of LC3II/I, Beclin-1, and ATG5 expression. Moreover, in HG-induced HK-2 cells, DMDD suppressed the overexpression of GRP78, CHOP, LC3II/I, Beclin1, and ATG5. Notably, IRE1α overexpression significantly increased autophagy incidence; however, DMDD treatment subsequently reduced the expression of LC3II/I, Beclin1, and ATG5.
DMDD effectively inhibits excessive ERS and autophagy, thereby reducing renal cell apoptosis through the IRE1α pathway and Ca pathway.
研究表明，杨桃具有治疗糖尿病及相关并发症的潜力。然而，从杨桃中分离出的2-十二烷基-6-甲氧基环己-2,5-二烯-1,4-二酮（DMDD）对糖尿病肾病（DN）的具体有益作用和分子机制仍需进一步研究。
80只C57BL/6 J雄性小鼠先进行1周的适应性喂养，随后给予高脂饮食并腹腔注射100 mg/kg链脲佐菌素（STZ）以构建体内DN模型。此外，将高糖（HG）诱导的人肾近端小管上皮细胞（HK-2）用作体外DN模型。通过蛋白质免疫印迹法、流式细胞术、免疫荧光法和酶联免疫吸附测定（ELISA）染色检测肾小管细胞中上皮-间质转化（EMT）、内质网应激（ERS）和自噬相关蛋白的表达水平。进行转录组分析以阐明DMDD通过抑制ERS和自噬减轻DN的具体机制。用IRE1α过表达慢病毒转染HK-2细胞以揭示IRE1α过表达在HG诱导的HK-2中的作用。
实验数据表明，DMDD可显著降低DN小鼠的血糖水平并改善肾脏病理改变。此外，DMDD抑制钙（Ca）途径，表现为自噬体形成减少以及LC3II/I、Beclin-1和ATG5表达下调。此外，在HG诱导的HK-2细胞中，DMDD抑制GRP78、CHOP、LC3II/I、Beclin1和ATG5的过表达。值得注意的是，IRE1α过表达显著增加自噬发生率；然而，DMDD处理随后降低了LC3II/I、Beclin1和ATG5的表达。
DMDD有效抑制过度的ERS和自噬，从而通过IRE1α途径和Ca途径减少肾细胞凋亡。
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