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Kidney Week

Abstract: PO0645

The Novel Soluble Guanylyl Cyclase (sGC) Activator Runcaciguat Attenuates Hypertensive Cardiorenal Rat Diseases

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

  • Benardeau, Agnes M., Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Stasch, Johannes-Peter, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Hahn, Michael G., Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Meyer, Jutta, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Kraehling, Jan R., Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Eitner, Frank, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Sandner, Peter, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
Background

Chronic kidney disease (CKD) is often associated with arterial hypertension, leading to the development of hypertensive nephropathy and ultimately kidney failure that is poorly prevented by current treatment options. Hypertension and nephropathy are associated with impaired NO/sGC/cGMP signaling, low cGMP production and increased oxidative stress. Runcaciguat is a novel potent and selective, NO- and heme-independent sGC activator. Here we investigated the therapeutic potential of Runcaciguat in rat models of hypertension associated chronic kidney disease.

Methods

Hypertensive rats (Sprague Dawley, 12-13 weeks old male, n=13/ group, angiotensin II (ANG) minipumps, 450ng/kg/min) were treated orally twice daily for 2 weeks with Runcaciguat (0.3, 1 or 3 mg/kg), losartan (30 mg/kg) or placebo. In a second study, male Renin-transgenic rats (mRen2/27, 8 weeks old, L-NAME 30-50 mg/L, n=18-24/group) were treated twice daily orally for up to 8 weeks with Runcaciguat (1, 3 or 10 mg/kg) or placebo. Key outcome parameters included mortality, blood pressure (BP), proteinuria, kidney histology, kidney and heart biomarkers and kidney gene expression.

Results

In the 2-week-treated ANG-rats, Runcaciguat dose-dependently and significantly reduced proteinuria without changing BP. Losartan significantly decreased BP and proteinuria. Runcaciguat reduced kidney LCN2 (NGAL) expression. In the 8-week-treated Renin-transgenic rats, Runcaciguat significantly and dose-dependently improved mortality from 58% (placebo) to 56%, 39% and 28% (@ 1, 3, 10 mg/kg). At all tested doses, Runcaciguat significantly reduced kidney and heart hypertrophy and increased creatinine clearance. At the highest dose, Runcaciguat also significantly reduced BP and proteinuria.

Conclusion

The novel oral sGC activator Runcaciguat exhibits cardiorenal protection and improved survival in hypertensive rat models. Our data strongly suggest that Runcaciguat represents a promising treatment option for hypertensive kidney disease patients.

Funding

  • Private Foundation Support