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

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.