2. Academic Validation
  3. Morus alba L. (Sangzhi) alkaloids alleviate diabetic nephropathy by suppressing endoplasmic reticulum stress and modulating AMPK-associated phosphatidylethanolamine content

Morus alba L. (Sangzhi) alkaloids alleviate diabetic nephropathy by suppressing endoplasmic reticulum stress and modulating AMPK-associated phosphatidylethanolamine content

  • Phytomedicine. 2026 Mar:152:157836. doi: 10.1016/j.phymed.2026.157836.
Shan Zhang 1,  Zhige Wen 2,  Xinyao Xu 3,  Yang Zhou 4,  Yupeng Chen 5,  Yueying Zhang 6,  Zunqi Kan 7,  Jialing Wang 8,  Bingrong Wu 9,  Cong Chen 10,  Qing Ni 11
Affiliations

Affiliations

  • 1 Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China. Electronic address: [email protected].
  • 2 Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China. Electronic address: [email protected].
  • 3 Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China. Electronic address: [email protected].
  • 4 Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China. Electronic address: [email protected].
  • 5 Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China. Electronic address: [email protected].
  • 6 Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China. Electronic address: [email protected].
  • 7 Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China. Electronic address: [email protected].
  • 8 Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China. Electronic address: [email protected].
  • 9 Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China. Electronic address: [email protected].
  • 10 Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing, 100053, China. Electronic address: [email protected].
  • 11 Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China. Electronic address: [email protected].
PMID: 41570782 DOI: 10.1016/j.phymed.2026.157836
Abstract

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.

Keywords

AMPK; Diabetic nephropathy; Endoplasmic reticulum stress; Lipid metabolism; Morus alba L. (Sangzhi) alkaloids; PE synthesis.

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