Verbascoside targets endothelial HIF-1α/ Lysyl oxidase signaling to attenuate glomerular injury in diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) drives progressive renal fibrosis and functional decline, ultimately leading to end-stage renal disease. Pathological crosstalk between glomerular endothelial cells and mesangial cells is increasingly recognized as central to DN progression. However, whether endothelial-derived signaling specifically drives mesangial injury under diabetic conditions remains undefined. METHODS: We applied multi-omics profiling to identify pathogenic drivers. Target validation included qPCR and immunofluorescence co-localization in renal tissues. In vitro endothelial-mesangial crosstalk was modeled using conditioned media (CM) from mouse GECs applied to mesangial cells. Verbascoside (VB) was screened via structure-based virtual docking against LOX/LOXL2 and binding affinity (KD) confirmed by biolayer interferometry (BLI). In vivo therapeutic efficacy of VB was assessed in db/db mice. RESULTS: LOX/LOXL2 was robustly upregulated in diabetic endothelia. Inhibiting endothelial-derived LOX/LOXL2 or HIF-1α in GECs attenuated HG-induced mesangial dysfunction by reducing proliferation/viability, oxidative stress, and fibrosis. Mechanistically, HIF-1α drove LOX/LOXL2 expression. VB was identified as a novel dual LOX/LOXL2 inhibitor. VB-CM mitigated mesangial injury in vitro. VB treatment improved renal function, reduced oxidative damage, and ameliorated fibrosis. CONCLUSION: Endothelial HIF-1α/LOX signaling drives mesangial oxidative stress and fibrosis in DN. Verbascoside, a dual LOX/LOXL2 inhibitor, represents a promising therapeutic agent targeting this pathogenic axis.