Kidney Week

Abstract: PO0917

The Novel Soluble Guanylyl Cyclase (sGC) Activator Runcaciguat Improves Cardiorenal Morbidity in a Diabetic Rat Model of CKD

Session Information

• Diabetic Kidney Disease: Basic Mechanisms
  October 22, 2020 | Location: On-Demand
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Benardeau, Agnes M., Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany

Agnes M. Benardeau,

• Stasch, Johannes-Peter, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany

Johannes-Peter Stasch,

• Hahn, Michael G., Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany

Michael G. Hahn,

• Pavkovic, Mira, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany

Mira Pavkovic,

• Mathar, Ilka, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany

Ilka Mathar,

• Kraehling, Jan R., Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany

Jan R. Kraehling,

• Eitner, Frank, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany

Frank Eitner,

• Sandner, Peter, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany

Peter Sandner,

Background

Patients with chronic kidney disease (CKD) and Type-2-Diabetes (T2D) have a high risk of kidney failure and cardiovascular events. CKD and T2D are associated with oxidative stress impairing NO/sGC signaling thus driving CKD progression. Runcaciguat is a novel potent and selective, sGC activator able to restore sGC signaling by activating the oxidized and heme-free sGC. Here we investigated the therapeutic potential of Runcaciguat in a rat model of T2D associated CKD.

Methods

Cardiorenal morbidity was studied in diabetic and proteinuric rats. Rats (ZDF/Crl-Lebr-fa/fa, 22 weeks old male, n=20/group) were treated orally for up to 42 weeks with Runcaciguat (3 mg/kg) or placebo. Key outcome parameters included mortality, blood pressure, proteinuria, kidney histology, biomarkers of kidney and heart damages, and gene expression.

Results

Proteinuria steadily increased over time in the placebo arm (uPCR (g/mmol) 0.9±0.1 @ baseline, 1.8±0.1 @12 wk, 5.9±0.7 @42 wk)) and was significantly reduced in the Runcaciguat arm (0.8±0.1 @ 12 wk, 3.0±0.5 @ 42 wk). Improved proteinuria was paralleled by significantly improved glomerular filtration rates @ 42 wk (55±5 ml/min vs. 36±9 in the placebo arm). Histological examination of kidney revealed that Runcaciguat strongly reduced tubular dilation, glomerulopathy and accumulation of protein cylinders. Runcaciguat significantly improved left ventricular heart weight as well as several kidney and heart injury markers in urine and in plasma.

Conclusion

The novel sGC activator Runcaciguat improved kidney and heart function and structure in a preclinical diabetic and hypertensive rat model and may become an effective treatment option for diabetic and chronic kidney disease patients.

Funding

• Private Foundation Support