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LipoxinA4 analog BML-111 protects podocytes cultured in high-glucose medium against oxidative injury via activating
Hua Hao1, Fangping Xie2, Fen Xu3
1Department of Pathology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, PR China.
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.
Insights
The Nrf2 pathway protects against oxidative stress. Lipoxin A4 analog BML-111 activates Nrf2, reducing diabetic kidney injury and podocyte damage by inhibiting inflammation and oxidative stress.
Area of Science:
- Nephrology
- Diabetology
- Molecular Biology
Background:
- The Nrf2 pathway is crucial for mitigating oxidative stress and podocyte injury in diabetic nephropathy.
- Lipoxin A4 (LXA4), a lipid mediator, exhibits antioxidant properties and may offer therapeutic benefits.
Purpose of the Study:
- To investigate whether BML-111, a lipoxin A4 analog, protects diabetic podocytes from oxidative injury by modulating the Nrf2 pathway.
- To elucidate the mechanisms underlying BML-111's protective effects in diabetic podocytes and kidneys.
Main Methods:
- In vitro studies using the MPC5 podocyte cell line exposed to high glucose (HG).
- In vivo studies in diabetic mouse models.
- Assessment of Nrf2 activation, phase II enzyme expression (Nqo1, Ho-1), cell migration, inflammatory markers (Vcam, Icam, Il-1α, Il-6, Tnf), blood glucose levels, and kidney damage.
Main Results:
- BML-111 inhibited HG-induced oxidative injury in MPC5 cells by activating Nrf2 and its downstream enzymes (Nqo1, Ho-1).
- BML-111 suppressed MPC5 cell migration and reduced inflammatory markers.
- In diabetic mice, BML-111 improved blood glucose levels and ameliorated kidney damage, mediated by Nrf2 activation via the Fpr2 receptor.
Conclusions:
- BML-111 demonstrates significant protective effects against diabetic podocyte and kidney injury.
- The mechanism involves the activation of the Nrf2 pathway and subsequent reduction in oxidative stress and inflammation.
- BML-111 represents a potential therapeutic agent for diabetic nephropathy.
