Abstract: SA-PO595
Tris DBA Ameliorates IgA Nephropathy by Blunting the Activating Signal of NLRP3 Inflammasome Through SIRT1- and SIRT3-Mediated Autophagy Induction
Session Information
- Glomerular Diseases: Immunology, Inflammation - II
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1202 Glomerular Diseases: Immunology and Inflammation
Authors
- Chung-Yao, Wu, Graduate Institute of Life Scieces National Defense Medical Center, Taipei, Taiwan
- Chen, Ann, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taipei, Taiwan
Background
Tris (Dibenzylideneacetone) dipalladium (Tris DBA), a small molecule palladium complex, can inhibit cell growth and proliferation in pancreatic cancer, lymphocytic leukemia and multiple myeloma. Given that this compound is particularly active against B cell malignancies (Chronic lymphocytic leukemia and multiple myeloma), we hypothesized that it can alleviate immune complex-mediated conditions, including IgA nephropathy (IgAN)
Methods
C57BL/6 mice were induced IgAN by consecutive 28 daily injections of purified IgA anti-phosphorylcholine antibodies and pneumococcal C-polysaccharide antigen (PnC), followed by clinical, pathological, and molecular mechanism analyses. On day 7 after disease induction, the mice were divided into 2 groups and administered daily either Tris DBA (30 mg/kg body weight) or vehicle (KATIMIN) via an intraperitoneal route throughout the study. The animals were killed at days 14 and 28, respectively. Cultured of macrophages were analysis for activating signal of NLRP3 inflammasome and SIRT1- and SIRT3-mediated autophagy induction.
Results
In the present study, we examined the therapeutic effects of Tris DBA on glomerular cell proliferation and renal inflammation in a mouse model of IgAN. The results show that treatment of IgAN mice with Tris DBA resulted in markedly improved renal function, albuminuria and renal pathology, including glomerular cell proliferation, neutrophil infiltration, sclerosis and peri-glomerular inflammation in the renal interstitium, together with [1] reduced mitochondrial ROS generation; [2] differentially regulated autophagy and NLRP3 inflammasome, [3] inhibited phosphorylation of JNK, ERK, and p38 MAPK signaling pathways, and priming signal of the NLRP3 inflammasome, and [4] blunted NLRP3 inflammasome activation through SIRT1- and SIRT3-mediated autophagy induction, in renal tissues or macrophages.
Conclusion
Tris DBA was able to effectively ameliorate the mouse IgAN model; this beneficial effect involves blunting of mitochondrial ROS production, a MAPK (ERK, JNK)-mediated priming signal of the NLRP3 inflammasome, and differentially regulating the autophagy/NLRP3 inflammasome axis through SIRT1 and SIRT3. Thus, Tris DBA can be considered a therapeutic candidate for IgAN.