Targeted Delivery of Triptolide Alleviates Diabetic Nephropathy via Inactivation of JAK2-STAT1 Signaling.
Year: 2025
Type: article
Abstract: Objective: Inflammation and fibrosis are key features of diabetic nephropathy (DN). Triptolide (TP) exhibits anti-inflammatory and anti-fibrotic properties, though its mechanisms of action in DN remain unclear. CREKA (Cys-Arg-Glu-Lys-Ala) is a pentapeptide that specifically binds to fibronectin (FN), and the CREKA-modified liposome (CREKA-Lip) represents a novel FN-targeted drug delivery system. This study aimed to investigate the role of TP in diabetic db/db mice and determine whether encapsulation within CREKA-Lip enhances therapeutic efficacy while reducing the multi-organ toxicity of TP. Methods: Eight-week-old diabetic db/db mice received tail vein injections twice weekly with vehicle, free TP, or CREKA-Lip/TP for 10 weeks. Urine and serum parameters were measured, and kidney, heart, liver, and testis tissues were collected for pathological evaluation. Protein-protein interaction networks were constructed using Cytoscape and its plug-ins to identify core targets and elucidate the therapeutic mechanism of TP against DN. Inflammatory, fibrotic, apoptotic, and lipid metabolism markers were evaluated in the kidneys of diabetic mice with DN and in high glucose-treated mouse mesangial cells and podocytes using qPCR, Western blot, immunohistochemistry, and immunofluorescence assays. Results: , TP inhibited high glucose-induced phosphorylation of JAK2 and STAT1, reduced collagen production in mesangial cells, decreased apoptosis, and improved lipid metabolism in podocytes. Moreover, CREKA-Lip/TP exhibited superior efficacy compared with free TP, with a more sustained reduction in urine albumin-to-creatinine ratio and greater inhibition of mesangial expansion. Notably, CREKA-Lip/TP treatment did not induce systemic toxicity. Conclusion: TP improves renal inflammation, fibrosis, apoptosis, and lipid homeostasis, thereby ameliorating DN by inhibiting JAK2-STAT1 activation. Targeted delivery of TP via FN-binding CREKA-Lip enhances therapeutic efficacy while minimizing multi-organ toxicity.
Source: PubMed
DOI: 10.12182/20250760503
Institutions: Sichuan University, West China Hospital of Sichuan University
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4415356144