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Kidney Week

Abstract: PO0600

The Novel Soluble Guanylyl Cyclase (sGC) Activator Runcaciguat Induced Renal Vasodilation and Reduced Kidney Damage in a Rat CKD Model

Session Information

  • CKD Mechanisms - 1
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Benardeau, Agnes M., Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Hahn, Michael G., Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Gerisch, Michael, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Meyer, Michaela, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Menshykau, Dzianis, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Hetzel, Terence, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Schlender, Jan, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Hartmann, Elke, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Schomber, Tibor, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Patzak, Andreas, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Schweda, Frank, Universitat Regensburg, Regensburg, Bayern, Germany
  • Kraehling, Jan R., Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Sandner, Peter, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Eitner, Frank, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
Background

CKD progression is associated with impaired NO/sGC/cGMP-signaling, low cGMP production and increased oxidative stress. Oxidative stress modifies the native sGC to oxidized, heme-free apo-sGC which cannot be activated by NO anymore. Runcaciguat is a novel potent and selective sGC activator that binds and activates heme-free sGC independently of NO and restores NO/sGC/cGMP signaling. We investigated the effects of Runcaciguat on intrarenal hemodynamics and in a rat model of T2D-associated CKD.

Methods

Hemodynamic effects were analyzed ex vivo in isolated renal afferent/efferent arterioles and in perfused kidneys. Effect of Runcaciguat on kidney protection was evaluated in diabetic and proteinuric rats. ZSF1 rats (12w, male, n=6/gp) were implanted with telemetry systems and treated daily orally for up to 12 weeks with Runcaciguat, Enalapril or placebo. Key parameters included proteinuria, kidney structural changes, biomarkers, kidney gene expression, systemic hemodynamics, and substance plasma exposures.

Results

Runcaciguat dilated renal afferent/efferent arterioles under NO depletion and increased blood flow, GFR and cGMP production in NO-depleted, isolated perfused kidneys. In ZSF1 rats, Runcaciguat dose-dependently reduced proteinuria (-17%, -50%, -85% @ 1, 3, 10 mg/kg/bid) without changing mean arterial pressure at steady-state. The reduction of proteinuria was significantly higher than with Enalapril (-39%, -63% @ 20, 60 mg/kg/d) at doses significantly reducing systemic blood pressure. Runcaciguat reduced kidney structural damages and kidney and liver weight. Runcaciguat reduced glycosylated hemoglobin and plasma triglycerides while Enalapril did not. Metabolic improvement was accompanied by gene expression changes suggesting improvement of vascular and endothelial functions independently of interaction with the Renin-Angiotensin-Aldosterone system. Runcaciguat plasma concentration was dose-proportional after acute and chronic dosing.

Conclusion

Runcaciguat prevented further decline in kidney function and structure independent of blood pressure in CKD rats. Our data suggest that the novel sGC activator Runcaciguat represents a promising treatment option for CKD patients.

Funding

  • Private Foundation Support