Abstract: FR-PO692
Ramipril Therapy in Integrin α1-Null ARAS Mice Triples Lifespan: Mechanistic Clues From RNA-Seq Analysis
Session Information
- Glomerular Diseases: Podocyte Biology - I
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1304 Glomerular Diseases: Podocyte Biology
Authors
- Cosgrove, Dominic E., Boystown National Research Hospital, Omaha, Nebraska, United States
- Madison, Jacob D., Boystown National Research Hospital, Omaha, Nebraska, United States
- Meehan, Daniel T., Boystown National Research Hospital, Omaha, Nebraska, United States
- Wilhelm, Kevin O'Connor, Baylor College of Medicine, Houston, Texas, United States
- Gratton, MichaelAnne, Boystown National Research Hospital, Omaha, Nebraska, United States
- Samuelson, Gina C., Boystown National Research Hospital, Omaha, Nebraska, United States
- Fascianella, John A., Boystown National Research Hospital, Omaha, Nebraska, United States
Background
The standard of care for patients with Alport syndrome is ACE inhibitors. In ARAS mice, the ACE inhibitors double lifespan. In humans, ACE inhibitor treatment extends life as well. Any therapy developed must provide significant benefit over ACE inhibition alone. Here we show that integrin α1-null Alport (DKO) mice treated with ramipril live 3X longer than untreated ARAS mice. This effect may be the result of laminin 211-mediated suppression of the transcriptional regulator FOXC2, which reduces expression of nephrin and podocin.
Methods
DKO mice were treated with vehicle or ramipril starting at 4 weeks of age. Proteinuria and glomerular filtration rates were measured at 5-week intervals. Glomeruli were analyzed for laminin 211 deposition in the GBM and GBM ultrastructure analyzed by TEM. RNA-seq was performed on isolated glomeruli at various timepoints, and cultured podocytes were overlayed with recombinant laminin 211 or not and RNA analyzed by RNA-seq.
Results
GFR in DKO mice decline between 10 and 15 weeks of age and in ramipril-treated DKO mice at 30 to 35 weeks. Proteinuria followed these same patterns with normalization of GBM architecture in ramipril-treated DKO mice. RNA-seq analysis showed that alteration of gene expression and pathways were similar comparing DKO with ramipril-treated DKO mice with delayed effects in ramipril-treated DKO mice. Decline in expression of nephrin and podocin mRNA and protein occurred but was delayed in the ramipril-treated DKO mice. GBM accumulation of laminin 211 was delayed in ramipril-treated Alport mice, and laminin 211 treatment of podocytes reduced expression of FOXC2 nephrin, and podocin.
Conclusion
Ramipril synergizes with integrin α1 blockade slowing the progression of glomerular disease and tripling the lifespan compared to untreated ARAS mice. The slowed progression involves similar genes and pathways, particularly the transcriptional regulator FOXC2, nephrin, and podocin. Reduced accumulation of laminin 211 in the GBM in treated mice. In vitro, Cultured podocytes exposed to laminin 211 show changes similar to Alport glomeruli.
Funding
- Other NIH Support