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Kidney Week

Abstract: PO0646

The Novel Nonsteroidal and Selective Mineralocorticoid Receptor Antagonist Finerenone Differentiates from SGLT2 Inhibitor Empagliflozin by Anti-Fibrotic Effects in a Progressive Mouse Kidney Fibrosis Model

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

  • Droebner, Karoline, Bayer AG, Wuppertal, Germany
  • Pavkovic, Mira, Bayer AG, Wuppertal, Germany
  • Grundmann, Manuel, Bayer AG, Wuppertal, Germany
  • Hartmann, Elke, Bayer AG, Wuppertal, Germany
  • Goea, Laura, Bayer AG, Wuppertal, Germany
  • Nordlohne, Johannes, Bayer AG, Wuppertal, Germany
  • Eitner, Frank, Bayer AG, Wuppertal, Germany
  • Kolkhof, Peter, Bayer AG, Wuppertal, Germany
Background

Finerenone and SGLT2 inhibitors have demonstrated clinical benefits in CKD patients with T2D. Cellular and molecular mechanisms responsible for these benefits are incompletely understood. MR-signaling has been linked to fibrosis in vitro via plasminogen activator inhibitor-1 (PAI-1) modulation. Here we investigated potential effects and mechanisms in a relevant preclinical mouse kidney fibrosis model.

Methods

Kidney fibrosis was induced in mice via unilateral ureteral obstruction. In a series of experiments, mice (C57/Bl6J, 8 weeks old male, n=10-12/group) were treated orally for 10 days with the MR antagonist finerenone (3 and 10 mg/kg), the SGLT2 inhibitor empagliflozin (10 and 30 mg/kg), or in a direct comparison of both drugs. Interstitial myofibroblast accumulation was quantified via alpha-smooth muscle actin (αSMA) and interstitial collagen deposition via Sirius red fast green staining. Secondary analyses included kidney mRNA expression of inflammatory and fibrotic markers and pathways.

Results

Myofibroblast accumulation was dose-dependently reduced in finerenone-treated mice (-22% @ 3 mg/kg, p=0.1; -41% @ 10 mg/kg, p=0.002) as well as collagen deposition (-22% @ 3 mg/kg, p=0.1; -44% @ 10 mg/kg, p=0.001). These antifibrotic effects of finerenone on protein level were matched on mRNA expression level (including collagens type III and IV). In contrast, treatment with SGLT2 inhibitor strongly increased urinary glucose excretion but had neither significant effects on kidney myofibroblasts (0% @ 10 mg/kg, p=0.7; -10% @ 30 mg/kg, p>0.99) nor on collagen deposition (-6% @ 10 mg/kg, p=0.9; -9% @ 30 mg/kg, p=0.8). In finerenone-treated mice reduced kidney fibrosis was paralleled by reduced kidney PAI-1 expression (-19% @ 3mg/kg, p=0.3; -41% @ 10 mg/kg, p=0.002).

Conclusion

Finerenone has direct anti-fibrotic properties resulting in reduced myofibroblast and collagen deposition in a mouse model of progressive kidney fibrosis.

Funding

  • Commercial Support