Abstract: FR-PO996
Transcriptome-Based Discovery of Lysine Deacetylase Inhibition as a Novel Treatment Approach to Alport Syndrome
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - II
October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidney
- 1002 Genetic Diseases of the Kidney: Non-Cystic
Authors
- Williams, Vanessa R., University of Toronto, Toronto, Ontario, Canada
- Konvalinka, Ana, University Health Network, Toronto, Ontario, Canada
- Song, Xuewen, University Health Network, Toronto, Ontario, Canada
- John, Rohan, University Health Network, Toronto, Ontario, Canada
- Pei, York P., University Health Network, Toronto, Ontario, Canada
- Scholey, James W., University Health Network, Toronto, Ontario, Canada
Background
Alport syndrome (AS) is a hereditary progressive disorder caused by mutations in type IV collagen genes. It is characterized by early proteinuria and activation of the renin-angiotensin system (RAS). Few effective treatment approaches to AS are currently available. Therefore, we applied a drug repurposing strategy to examine a novel therapy.
Methods
RNA expression profiling of kidney cortices from Col4a3–/– (KO) and wild-type (WT) mice on a 129/SvJ background was performed at 4 and 7 weeks of age. A disease progression signature composed of differentially expressed genes was used to query the Connectivity Map (CMAP). CMAP identified vorinostat, a lysine deacetylase inhibitor, as a potential therapy. KO mice were treated with vorinostat (50 mg/kg/day in DMSO by oral gavage) from 4 to 7 weeks of age. Mice were euthanized at 7 weeks of age for kidney function, structure, inflammation, and fibrosis analyses. Separate groups were followed for assessment of lifespan. Finally, angiotensin II-stimulated human proximal tubule epithelial (HK-2) cells were treated with vorinostat (5 μM) and used to assess mechanisms of drug action.
Results
Vorinostat increased the acetylation of lysine in the kidney. This was associated with a significant increase in survival (n = 19/group) and a trend toward decreased serum creatinine and proteinuria (n = 6-10/group). Vorinostat had no effect on glomerulosclerosis, but significantly reduced urinary excretion of NGAL, a marker of tubular injury. mRNA for cytokines and kidney injury markers including Fn1, Havcr1, and Tnf were reduced in the kidneys of treated mice (n = 6/group). Kidney tissue protein analysis showed lowered αSMA and proinflammatory cytokine expression. Pilot mechanistic studies revealed that vorinostat exerts its beneficial effects, at least in part by, dampening mitogen-activated protein kinase (MAPK) signaling and subsequent activator protein 1 (AP-1) transcription factor activation.
Conclusion
CMAP analysis identified vorinostat as a novel therapy for AS. Testing of the putative therapy showed that it exerts renoprotective effects and extends the lifespan of KO mice. Future studies will provide more insight into the molecular mechanisms of vorinostat through assessment of lysine acetylation, and MAPK and AP-1 signaling pathways in the progression of AS nephropathy.
Funding
- Government Support - Non-U.S.