Puerarin Attenuated Excessive Extracellular Matrix Accumulation in Diabetic Nephropathy Through Inhibiting Glomerular Mesangial Cells Ferroptosis

The discovery of ferroptosis shed lights on mechanical research of diabetic nephropathy (DN). Puerarin (PUR) is reported to exert beneficial effects on DN, but the exact mechanism was unclear. In this study, we focused on glomerular mesangial cells (GMCs), the primary and initial site of chronic hyperglycemia injuries in DN, to investigate the effects of PUR on high glucose (HG) stress induced injuries and explore its mechanism, then verified in type 2 DN rat model. The results showed that 125 mM HG significantly induced GMCs impairments of losing cell viability, ROS production and excessive collagen fiber accumulation. Moreover, the characteristic phonotypes of ferroptosis including lipid ROS generation, LDH release, GSH disruption, Gpx4 degradation and iron overloading were observed, and were blocked by treatment with PUR (1 μM, 10 μM). Moreover, PUR ameliorated HG disturbed iron metabolism homeostasis by suppressing transferrin, transferrin receptor-1 and divalent metal transporter-1 induced iron uptake, elevating iron export by ferroportin-1 and improving intracellular iron storage and reducing the free ferrous iron overloading. Further investigations in DN rats vindicated that administration of PUR 100 mg/kg/day markedly reduced urinary albumin, ameliorated renal function, suppressed mesangial matrix expansion, and eventually retard renal fibrosis. Moreover, the increased iron overload and lipid peroxidation in DN kidneys were alleviated by PUR treatment. Taken together, these results provide compelling evidence that PUR plays a role in suppressing GMCs injuries during DN, partly through regulation on iron homeostasis to mitigate ferroptosis, suggesting a new mechanism of PUR as a potential therapy for DN.