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Kidney Week

Abstract: PO0623

Uncovering Genomic Alterations in DOCA-Salt Nephropathy Rats Treated with Finerenone

Session Information

  • CKD Mechanisms - 2
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Wu, Junnan, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Ma, Ziyuan, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Cernecka, Hana, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Lesche, Ralf, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Kolkhof, Peter, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background

The aldosterone antagonist spironolactone has antifibrotic effects but its clinical use is limited due hyperkalemia, especially in patients with kidney disease. The novel nonsteroidal and selective mineralocorticoid antagonist finerenone has recently been developed with pronounced antifibrotic activity at doses which have only limited effect on the potassium homeostasis. The exact molecular transcriptional targets of spironolactone and finerenone, however, remain unknown. Since there are more than 20 different cell types in the kidney, single cell RNA and single cell epigenome (ATAC) analysis can help to define transcriptional targets.

Methods

We treated uninephrectomized, Sprague-Dawley rats injected with DOCA and salt with a high dose of finerenone (10mg/kg/d), spironolactone (50mg/kg/d), or vehicle. Outcome parameters included blood pressure, serum and urine electrolytes, albuminuria, renal and cardiac histology. Single nuclei suspension was prepared from kidneys and hearts for single nuclear RNA and single nuclear open chromatin (ATAC) profiling using the 10X Genomics Chromium platform as well as bulk RNA sequencing.

Results

Finerenone and spironolactone resulted the same degree of blood pressure reduction. DOCA treated rats developed severe myocardial hypertrophy and focal vasculopathy, glomerulosclerosis and tubulointerstitial fibrosis. Finerenone significantly attenuated cardiac and renal histological damage. DOCA-salt rats developed marked albuminuria which was significantly attenuated by spironolactone and finerenone. Serum potassium was elevated in the spironolactone group at weeks 6, but it was unchanged compared to controls in the finerenone group. Bulk RNA-seq results revealed the reduced enrichment of immune response related transcripts in finerenone group compared with DOCA and spironolactone group. Single-nuclei open chromatin and gene expression profiling uncovered genomic alterations in different cell types in finerenone-treated kidneys.

Conclusion

Taken together, these findings demonstrated that treatment with finerenone protected from DOCA salt induced cardiac hypertrophy, glomerulosclerosis and kidney fibrosis without a significant increase in serum potassium. Single cell epigenome analysis highlighted transcriptional targets of aldosterone, spironolactone and finerenone.

Funding

  • NIDDK Support