LipoxinA4 analog BML-111 protects podocytes cultured in high-glucose medium against oxidative injury via activating Nrf2 pathway

Abstract

Numerous studies have shown that the activation of the Nrf2 pathway alleviates oxidative stress and podocyte damage. Emerging evidence indicates that the dual anti-inflammatory and pro-resolution lipid mediator, lipoxin A4 (LXA4), has antioxidant activity. The aim of the present study was to confirm that BML-111, an analog of LXA4, prevents oxidative injury in diabetic podocytes via the regulation of the Nrf2 pathway. Here, we found that BML-111 inhibited high glucose (HG)-induced oxidative injury in the podocyte cell line, MPC5, in vitro, through activating Nrf2. Mechanistically, BML-111 significantly activated Nrf2 and its phase II enzymes, including Nqo1 and Ho-1. Moreover, BML-111 suppressed the migration of MPC5 cells. Additionally, BML-111 decreased the expression of Vcam, Icam and inflammatory cytokines (Il-1α, Il-6, and Tnf) in MPC5 cells. Importantly, BML-111 ameliorated blood glucose levels (approximately 75% of that in the SMZ group) and kidney damage by activating Nrf2, and its phase II enzymes, in diabetic mice. These effects are mainly mediated by Fpr2, a specific LXA4 receptor. Our findings demonstrate that BML-111 alleviates the injury of diabetic podocytes and kidneys by regulating the Nrf2 pathway.