Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Morus alba L. (Sangzhi) alkaloids alleviate diabetic nephropathy by suppressing endoplasmic reticulum stress and modulating AMPK-associated phosphatidylethanolamine content.
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Zhang Shan, Wen Zhige, Xu Xinyao, Zhou Yang, Chen Yupeng, Zhang Yueying, Kan Zunqi, Wang Jialing, Wu Bingrong, Chen Cong, Ni Qing
Аннотация
BACKGROUND: Diabetic nephropathy (DN) is frequently characterized by significant alterations in lipid metabolism, a pathological condition that amplifies renal injury and accelerates disease progression. Sangzhi alkaloid (SZ-A), a major extract from Morus alba l., is clinically used in China for the treatment of type 2 diabetes mellitus. In addition to its antihyperglycemic effect, SZ-A has demonstrated protective activity in diabetic target organs and has shown promise in modulating lipid metabolic pathways.
PURPOSE: In this study, we examined the therapeutic role of SZ-A in DN, with particular focus on its regulation of phosphatidylethanolamine (PE) biosynthesis via AMP-activated protein kinase (AMPK) signaling.
METHODS: KK-Ay mice, a spontaneous model of early-stage DN, were treated with SZ-A for 12 weeks. Renal pathology was assessed by periodic acid-silver methenamine and hematoxylin-eosin staining, along with transmission electron microscopy. Renal lipid deposition and oxidative stress were evaluated by Oil Red O staining and immunohistochemical detection. Lipidomics and transcriptomics analyses were conducted to elucidate changes in PE synthesis and endoplasmic reticulum (ER) stress.
RESULTS: SZ-A significantly reduced blood glucose, 24-hour urinary protein excretion, and the albumin-to-creatinine ratio, indicating improvement in renal function. SZ-A also lowered circulating lipid levels and decreased ectopic lipid accumulation in renal tissues, correlating with alterations in PE metabolism. Mechanistically, SZ-A promoted AMPK activation, thereby increasing PE content and reducing the expression of ER stress-related proteins, including IRE1, pIRE1, EIF2α, pEIF2α, and ATF4. Silencing of the PE-synthesizing enzyme Pcyt2 by siRNA abolished these effects, confirming an associated link between PE regulation and ER stress attenuation under glucolipotoxic conditions.
CONCLUSION: This study finds that SZ-A significantly reduced diabetic kidney damage, acting primarily through the regulation of lipid metabolism mediated by AMPK signal.
PURPOSE: In this study, we examined the therapeutic role of SZ-A in DN, with particular focus on its regulation of phosphatidylethanolamine (PE) biosynthesis via AMP-activated protein kinase (AMPK) signaling.
METHODS: KK-Ay mice, a spontaneous model of early-stage DN, were treated with SZ-A for 12 weeks. Renal pathology was assessed by periodic acid-silver methenamine and hematoxylin-eosin staining, along with transmission electron microscopy. Renal lipid deposition and oxidative stress were evaluated by Oil Red O staining and immunohistochemical detection. Lipidomics and transcriptomics analyses were conducted to elucidate changes in PE synthesis and endoplasmic reticulum (ER) stress.
RESULTS: SZ-A significantly reduced blood glucose, 24-hour urinary protein excretion, and the albumin-to-creatinine ratio, indicating improvement in renal function. SZ-A also lowered circulating lipid levels and decreased ectopic lipid accumulation in renal tissues, correlating with alterations in PE metabolism. Mechanistically, SZ-A promoted AMPK activation, thereby increasing PE content and reducing the expression of ER stress-related proteins, including IRE1, pIRE1, EIF2α, pEIF2α, and ATF4. Silencing of the PE-synthesizing enzyme Pcyt2 by siRNA abolished these effects, confirming an associated link between PE regulation and ER stress attenuation under glucolipotoxic conditions.
CONCLUSION: This study finds that SZ-A significantly reduced diabetic kidney damage, acting primarily through the regulation of lipid metabolism mediated by AMPK signal.