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This is a Animal Study study (also classified as: Observational).

September 10, 2025Open Access

Schisandra chinensis Mixture Attenuates Diabetic Kidney Disease via VDAC1/Grp75/IP3R-Mediated MAMs Stabilization and Apoptosis-Autophagy Regulation

Key Points

Schisandra chinensis mixture significantly alleviates diabetic kidney disease through preservation of mitochondria-associated membranes.
MAMs integrity restoration improved renal function by reducing apoptosis and enhancing autophagy in high glucose conditions.
The protective effects were confirmed in both animal models and human renal tubular cells under simulated diabetic conditions.
Findings highlight the potential for MAMs stabilization as a therapeutic target in diabetic kidney disease management.

Abstract

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-IP3R axis, regulating HG-stimulated apoptosis and autophagy in renal tubular cells, improving mitochondrial function, and suppressing fibrotic progression.

Schisandra chinensis Mixture Attenuates Diabetic Kidney Disease via VDAC1/Grp75/IP3R-Mediated MAMs Stabilization and Apoptosis-Autophagy Regulation

Key Points

Abstract

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