Abstract: PO0650
Nrf2 Activators Induce Inflammasome Attenuation: Possible Role in Diabetic Nephropathy
Session Information
- Diabetic Kidney Disease: Basic - I
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Quevedo Romero, Ignacio Juan, Instituto Murciano de Investigacion Biosanitaria Virgen de la Arrixaca, Murcia, Región de Murcia, Spain
- Carrasco Cremades, Andrea, Instituto Murciano de Investigacion Biosanitaria Virgen de la Arrixaca, Murcia, Región de Murcia, Spain
- Navarro, Laura Hurtado, Instituto Murciano de Investigacion Biosanitaria Virgen de la Arrixaca, Murcia, Región de Murcia, Spain
- Pelegrin, Pablo, Instituto Murciano de Investigacion Biosanitaria Virgen de la Arrixaca, Murcia, Región de Murcia, Spain
- Cuevas, Santiago, Instituto Murciano de Investigacion Biosanitaria Virgen de la Arrixaca, Murcia, Región de Murcia, Spain
Group or Team Name
- Molecular Inflammation Group (IMIB-Arrixaca)
Background
Kidney diseases remain a worldwide public health problem characterized by sustained inflammation. Inflammasome has recently emerged as crucial regulators of renal inflammation. In particular, the NLRP3 inflammasome, is involved in the activation of caspase-1 and the maturation of IL-1β and IL-18, which have been strongly associated with diabetic nephropathy. DJ-1 is a redox-sensitive chaperone with reported antioxidant and anti-inflammatory properties in the kidney, in part due to the regulation of transcription factor Nrf2, which regulates the expression of several antioxidant genes. The 20 amino acid (aa) peptide ND-13, is a new experimental treatment that consists of 13 highly conserved aa from the DJ-1 sequence.
Methods
In this study, we determined NLRP3 inflammasome activation in peripheral blood mononuclear cells (PBMCs) of diabetic nephropathy patients and the capacity of Nrf2 inducers to attenuate inflammasome activation. Mouse bone marrow macrophages were treated with Bardoxolone (1µM), an Nrf2 inducer, and ND-13 (1µM) for 24 hours.
Results
The IL-1β concentration in the medium increased by the stimulation of the NLRP3 inflammasome by LPS/ATP, and decreased in macrophages pre-treated with Bardoxolone (65.07±26%,n=4, P<0.05) but not in macrophages pre-treated with ND-13. Concentration-response curve demonstrates the capacity of Bardoxolone to inhibit NLRP3 inflammasome activation by LPS/ATP. Additionally, in presence of H2O2 (100nM), ND-13 (1µM) significantly decreased IL-1β release after NLRP3 activation (88.6±1.2%, n=4, P<0.05), suggesting the capacity of the ND-13 peptide to reduce NLRP3 inflammasome activity under pathological conditions. PBMCs isolated from the blood of controls patients, patients with diabetes, and patients with diabetes and renal disease were cultured in vitro and stimulated with LPS/ATP. Compared to controls and diabetic individuals, patients with diabetic nephropathy presented a trend to increase IL-1β release.
Conclusion
All these data point out that inflammasome pre-activation could have a role in the pathogenesis of diabetic nephropathy, that Nrf2 pathway stimulation is a promising approach to decrease immune cells inflammasome pre-activation, and ND-13 could be a new approach to protect the renal damage associated to inflammasome over-activation in renal diseases.
Funding
- Government Support – Non-U.S.