Li Hongdian, Dong Ao, Liu Cong, He Pengfei, Ma Yu, Chen Shu, Dong Shaoning, Zhang Sai, Zhang Minying, Zhang Mianzhi
tianjin hospital of ITCWM nankai hospital, Tianjin Medical University, Tianjin, China; Yuquan Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China; Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China.
Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China; Fengtai District Hospital Management Center, Beijing, China.
Phytomedicine. 2025 Nov;147:157164. doi: 10.1016/j.phymed.2025.157164. Epub 2025 Aug 12.
Diabetic kidney disease (DKD) is a major cause of end-stage renal disease, with mitochondrial dysfunction-mediated tubular injury implicated in its pathogenesis. Mitochondria-associated membranes (MAMs) coordinate apoptosis and autophagy in diabetic tubular injury. While Schisandra chinensis Mixture (SM) shows renoprotective effects, its mechanism in counteracting hyperglycemia-induced tubular cell death and fibrosis via MAMs integrity remains unclear.
This study investigated whether SM alleviates renal fibrosis by restoring MAMs integrity under high glucose (HG) conditions, thereby regulating renal tubular cell apoptosis and autophagy.
DKD was induced in Sprague-Dawley rats through high-fat/high-glucose diet and streptozotocin injection, followed by 12-week treatment with SM (1.5/3/6 g/kg/d). Renal function, injury markers and histopathology were assessed. Apoptosis, autophagy, and fibrosis were characterized by immunohistochemical localization, western blotting quantification, and TUNEL assay. Mitochondria-endoplasmic reticulum (ER) interactions and MAMs integrity were evaluated through ultrastructural and molecular analyses. In vitro, the protective mechanism of SM was validated through lentiviral-mediated manipulation of MAMs integrity. Serum components of SM were characterized by ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS).
In DKD rats, SM treatment restored mitochondrial-ER ultrastructure and coupling, evidenced by enhanced interactions of MAMs tethering proteins. SM dose-dependently improved renal function, attenuated tubular apoptosis, restored HG-impaired autophagy, and mitigated fibrosis. In HG-stimulated HK-2 cells, SM similarly rescued mitochondrial-ER proximity and suppressed fibrotic markers. Lentiviral models further confirmed that SM alleviates tubular injury by preserving MAMs integrity. UPLC-MS/MS identified major serum constituents of SM (e.g., schisandrin C); their individual bioactivities were not assessed in this study.
SM treats DKD by MAMs integrity through the VDAC1-Grp75-IPR axis, regulating HG-stimulated apoptosis and autophagy in renal tubular cells, improving mitochondrial function, and suppressing fibrotic progression.
糖尿病肾病（DKD）是终末期肾病的主要病因，其发病机制与线粒体功能障碍介导的肾小管损伤有关。线粒体相关膜（MAMs）在糖尿病肾小管损伤中协调细胞凋亡和自噬。虽然五味子合剂（SM）具有肾脏保护作用，但其通过维持MAMs完整性来对抗高血糖诱导的肾小管细胞死亡和纤维化的机制仍不清楚。
本研究探讨SM是否通过在高糖（HG）条件下恢复MAMs完整性来减轻肾纤维化，从而调节肾小管细胞凋亡和自噬。
通过高脂/高糖饮食和链脲佐菌素注射诱导Sprague-Dawley大鼠发生DKD，随后用SM（1.5/3/6 g/kg/d）进行12周治疗。评估肾功能、损伤标志物和组织病理学。通过免疫组化定位、蛋白质印迹定量和TUNEL检测对细胞凋亡、自噬和纤维化进行表征。通过超微结构和分子分析评估线粒体-内质网（ER）相互作用和MAMs完整性。在体外，通过慢病毒介导的MAMs完整性操作验证了SM的保护机制。通过超高效液相色谱/串联质谱（UPLC-MS/MS）对SM的血清成分进行表征。
在DKD大鼠中，SM治疗恢复了线粒体-内质网超微结构和偶联，MAMs锚定蛋白相互作用增强证明了这一点。SM剂量依赖性地改善肾功能，减轻肾小管细胞凋亡，恢复HG损伤的自噬，并减轻纤维化。在HG刺激的HK-2细胞中，SM同样挽救了线粒体-内质网的接近度并抑制了纤维化标志物。慢病毒模型进一步证实，SM通过维持MAMs完整性减轻肾小管损伤。UPLC-MS/MS鉴定了SM的主要血清成分（如五味子丙素）；本研究未评估它们各自的生物活性。
SM通过MAMs完整性，经VDAC1-Grp75-IPR轴治疗DKD，调节HG刺激的肾小管细胞凋亡和自噬，改善线粒体功能，并抑制纤维化进展。
