Brown adipose tissue alleviates podocyte apoptosis through NRG4 in a male mouse model of diabetic kidney disease.

Summary

Using BAT-specific and global Nrg4 knockout mice, AAV-mediated NRG4 replenishment, BAT transplantation, and in vitro podocyte assays, the authors show that BAT-derived NRG4 reduces podocyte apoptosis and albuminuria in diabetic nephropathy. Mechanistically, protection is mediated via activation of the Akt–GSK-3β pathway.

Key Findings

• BAT-specific Nrg4 knockout increased podocyte apoptosis by ~47% and raised urinary albumin/creatinine ratio by ~42%.
• AAV-mediated NRG4 replenishment and BAT transplantation reversed apoptosis and albuminuria phenotypes in knockout mice.
• Recombinant NRG4 and co-culture with WT brown adipocytes protected podocytes from high-glucose–induced apoptosis via Akt–GSK-3β signaling.

Clinical Implications

While preclinical, the findings suggest that enhancing NRG4 signaling or BAT function could become a strategy to reduce albuminuria and podocyte injury in diabetic kidney disease. It also supports metabolic interventions that activate BAT as potentially renoprotective.

Limitations

• Findings are preclinical and based on male mouse models; human translatability remains to be established.
• The long-term systemic effects and safety of modulating NRG4/BAT activity were not assessed.

Future Directions

Define NRG4 receptor targets on podocytes, evaluate NRG4 analogs or BAT activators in large-animal models, and conduct biomarker-guided early phase trials in diabetic kidney disease.