Abstract: PO2521
Revealing the Antifibrotic Mechanism of Finerenone in the DOCA-Salt Nephropathy Rat Model Using Single Nuclei and Bulk Transcriptomics
Session Information
- CKD: Metabolism, Epigenetics, and Signaling
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Abedini, Amin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Wu, Junnan, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Ma, Ziyuan, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Frederick, Julia, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Cernecka, Hana, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
- Kolkhof, Peter, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
- Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background
Finerenone is a nonsteroidal mineralocorticoid receptor antagonist (MRA) which has been proposed to possess pronounced antifibrotic efficacy with a reduced risk to develop hyperkalemia in comparison to steroidal MRAs. However, the exact mechanism of this investigational medication has not been revealed. Single nuclei RNA-sequencing by determining the transcriptional signature at single cell level is an emerging method for elucidating the molecular mechanism of drug action.
Methods
Uninephrectomized, Sprague-Dawley rats were treated with DOCA and salt with an equivalent antihypertensive dose of finerenone (10mg/kg/d), spironolactone (50mg/kg/d), or vehicle. Kidney interstitial fibrosis was considered as outcome. Single nuclei RNA-seq using 10X Genomics Chromium platform in 11 and bulk RNA-seq in 14 specimens were generated.
Results
Interstitial fibrosis was significantly lower in the finerenone group than rats who received DOCA or spironolactone. Unbiased clustering was performed on 85’661 nuclei. All kidney cell types were represented in the final dataset. Comparison of cell type fractions in each group demonstrated that injured and proliferative proximal tubule (PT) cells as well as principal cells of the collecting duct and immune cells were significantly different. Side by side comparison of differential gene expression in PT cells demonstrates that finerenone normalizes genes involved in metabolic processes. Trajectory analysis on the PT cells indicates that PT cells in DOCA and spironolactone treated rats are more susceptible to the injury and transforming to injured PT cells. The results of bulk RNA-seq analysis is consistent with single nuclei transcriptomics indicating the normalization of the genes enriched in metabolic processes and immune responses by finerenone.
Conclusion
Overall, our results demonstrate that treatment with finerenone protects the kidney from interstitial fibrosis. Using single nuclei and bulk transcriptomics revealed that the protection of the PT cells via normalizing the expression of genes which are enriched in metabolic processes and immune response could be a putative further protective mechanism of finerenone in renal diseases.