Abstract: TH-PO266
Antisense Oligonucleotide Mediated Inhibition of NLRP3 Expression Attenuates Aristolochic Acid Induced AKI
Session Information
- AKI Basic: Inflammation and Transcription
November 02, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Acute Kidney Injury
- 001 AKI: Basic
Authors
- Donner, Aaron, Ionis Pharmaceuticals, Carlsbad, California, United States
- Bell, Thomas, Ionis Pharmaceuticals, Carlsbad, California, United States
- Graham, Mark, Isis Pharmaceuticals, Carlsbad, California, United States
- Crooke, Rosanne M., Ionis Pharmaceuticals, Inc, Carlsbad, California, United States
Background
In addition to its role in innate immunity, there is increasing evidence that the inflammasome pathway is a crucial driver of pathology in immune, metabolic and renal diseases. Genetic and pharmacologic inhibition of components of the NLRP3-containing inflammasome (NLRP3, ASC and Caspase-1) or its downstream effectors (IL-1b, IL-18) has been shown to provide therapeutic benefit in animal models of disease. We have sought to target the upstream node, the inflammasome, using ASOs directed against NLRP3 in a mouse model of acute kidney disease. We demonstrated the ability to prevent aristolochic acid I induced acute kidney injury (AAI AKI) with prior administration of an ASO targeting NLRP3, a key component of the inflammasome. The NLRP3 ASO attenuated disease based on plasma and urinary biomarkers, renal expression of inflammatory and pro-fibrotic mRNA markers and histological changes. Disease-induced increases in plasma creatinine and BUN and urinary increases in protein:creatinine ratios were reduced by prior administration of NLRP3 ASO. AAI dependent induction of renal inflammatory (e.g. nlrp3, kim1, ngal) and pro-fibrotic (e.g. timp1, mmp2, col1a1) mRNAs was also reduced by the NLRP3 ASO. Histologically, the NLRP3 ASO protected from AAI induced morphological changes throughout the nephron. Based on our findings, ASO mediated inhibition of NLRP3 expression could provide therapeutic benefit for those suffering from kidney disease.