Hederagenin Improves Adriamycin-induced Nephropathy by Inhibiting the JAK/STAT Signaling Pathway

Abstract

ABSTRACT Background: Glomerulonephritis, a common kidney disease and major cause of end-stage renal disease, lacks effective treatment options. Hederagenin (HDG) exerts potent anti-inflammatory and protective effects on the kidneys and exhibits promise for the treatment of glomerulonephritis. This study aimed to investigate the therapeutic effects and mechanism of action of hederagenin in the context of adriamycin-induced nephropathy (ADN). Methods: C57BL/6 mice were randomly divided into 5 groups that included the control, model, low-dose HDG (20 mg/kg), high-dose HDG (40 mg/kg), and positive control (10 mg/kg irbesartan) groups. ADN was established in mice by administering a single injection of 10 mg/kg adriamycin. Renal pathology and fibrosis were assessed using haematoxylin and eosin (H & E) and Masson’s trichrome staining, whereas in vitro studies were conducted using cultured mouse podocytes (MPC5). Immunofluorescence staining and western blotting were performed to detect inflammation and the protein levels of signaling pathways. Results: The results revealed that HDG significantly improved adriamycin-induced abnormal serum creatinine, albumin, and urea nitrogen levels. HDG treatment reduced glomerular injury and fibrosis, particularly at high doses. Additionally, HDG effectively reduced adriamycin-induced activation of Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling and renal fibrosis while suppressing CD4+/CD8+ cell ratios in the kidneys and enhancing the immune response. Interestingly, when the JAK/STAT signaling pathway was activated by an agonist, the ameliorative effects of HDG on ADN were inhibited, thus suggesting that JAK/STAT signaling is a key target of HDG. Conclusion: HDG may represent a promising treatment option for glomerulonephritis by inhibiting JAK/STAT-mediated immune-inflammatory responses.