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Abstract: TH-PO249

ND-13, a DJ-1 Derived Peptide, as a Novel Pharmacological Approach to Activated Nrf2 in the Prevention of Inflammasome Activation in Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 602 Diabetic Kidney Disease: Clinical

Authors

  • Cuevas, Santiago, BioMedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Región de Murcia, Spain
  • Sanchez, Virginia Celdran, BioMedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Región de Murcia, Spain
  • Luna García, Adrián, BioMedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Región de Murcia, Spain
  • Kupchyk, Maksym, BioMedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Región de Murcia, Spain
  • Andugar-Rocamora, Leonor, Clinical University Hospital Virgen de la Arrixaca, Murcia, Region de Murcia, Spain
  • López, Cristina Molina, BioMedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Región de Murcia, Spain
  • Ros Madrid, Inmaculada, Clinical University Hospital Virgen de la Arrixaca, Murcia, Region de Murcia, Spain
  • Navarro, Laura Hurtado, BioMedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Región de Murcia, Spain
  • Rosique, Florentina, Clinical University Hospital Virgen de la Arrixaca, Murcia, Region de Murcia, Spain
Background

The inflammasome is a crucial regulator of renal inflammation and a key factor in the pathogenesis of renal diseases. DJ-1 is a renal protein with antioxidant and anti-inflammatory properties with the capacity to prevent Nuclear factor erythroid 2-related factor 2 (Nrf2) degradation. Nrf2 is a transcription factor that activates the expression of numerous proteins with antioxidant properties. ND-13 is a peptide consisting of 13 highly conserved aas from the DJ-1 sequence. In this study, we determined the capacity of ND-13/Nrf2 pathway to attenuate inflammasome activation in renal diseases.

Methods

Mouse bone marrow macrophages (BMM) were treated with Bardoxolone, an Nrf2 inducer, and ND-13. Diabetes was induced in C57Bl/6 mice via injection of STZ and treated with ND-13. Peripheral blood mononuclear cells (PBMCs) were isolated from the blood of patients with diabetic nephropathy and controls and were plate and stimulated with LPS/ATP and treated with ND-13 and MCC950, an inflammasome inhibitor.

Results

The IL-1β concentration in the medium of BMM increased by NLRP3 inflammasome stimulation by LPS/ATP, and decreased in macrophages pre-treated with Bardoxolone (65.07±26%, n=4, P<0.05) but not pre-treated with ND-13, however, in presence of H2O2 (100nM), ND-13 significantly decreased IL-1β release after NLRP3 activation (88.6±1.2%, n=4, P<0.05). These data were confirmed by Bardoxolone and ND-13 concentration-response curve. Peritoneal macrophages from diabetic mice were obtained and plated. STZ treatment increased the IL-1β production compared with the control, suggesting that inflammasome may be activated in diabetes and ND-13 treatment normalized its activity. PBMCs isolated from the blood of patients were plate and stimulated with LPS/ATP, and patients with diabetic nephropathy presented a trend to increase IL-1β release compared to controls and diabetic individuals and ND-13 could have a role in the prevention of inflammasome activation.

Conclusion

All these data point out that DJ-1/Nrf2 pathway stimulation is a promising approach to decreasing immune cells inflammasome activation, and ND-13 could be a new approach to attenuate inflammation in renal diseases.

Funding

  • Government Support – Non-U.S.