Abstract: PO2510
Comparison of the Renal Effects of Heme-Dependent and Independent Soluble Guanylate Cyclase Targeting Drugs in 5/6 Nephrectomized Rats on High-Salt Diet
Session Information
- CKD: Metabolism, Epigenetics, and Signaling
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Xiong, Yingquan, Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
- Zeng, Shufei, Department of Nephrology, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
- Hasan, Ahmed A., Institute of Nutritional Science, University of Potsdam, Potsdam, Germany
- Delic, Denis, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
- Gaballa, Mohamed Mahmoud Salem Ahmed, Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
- Pavkovic, Mira, Bayer AG, Pharmaceuticals R&D, Pharma Research Center, Wuppertal, Germany
- Sandner, Peter, Bayer AG, Pharmaceuticals R&D, Pharma Research Center, Wuppertal, Germany
- Krämer, Bernhard K., Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
- Hocher, Berthold, Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
Background
Soluble guanylate cyclase (sGC) targeting drugs were reported to have beneficial renal effects in chronic kidney disease (CKD). The sGC stimulators bind to reduced, heme-containing sGC, while sGC activators bind to oxidized, heme-free sGC and their actions are heme-independent. Regarding renal outcomes, the potential differences between these two classes of drugs are unknown so far. This study aimed to provide a head-to-head comparison of the renal effects of BAY 41-8543 (sGC stimulator) and BAY 60-2770 (sGC activator) in 5/6 nephrectomized rats on high salt diet as a model of CKD.
Methods
Rats were allocated to the following groups: Sham + normal diet + placebo (PBO); 5/6Nx + 2 % high salt diet (HSD) + PBO; 5/6Nx + HSD + Telmisartan (5mg/kg/day); 5/6Nx + HSD + BAY 60-2770 (1mg/kg/day); 5/6Nx + HSD + BAY 41-8543 (1mg/kg/day). The treatment period was 8 weeks.
Results
Blood pressure was significantly decreased by BAY 60-2770 and BAY 41-8543 versus placebo (-32.52/-27.20 mmHg, p<0.001; -23.83/-29.90 mmHg, p<0.001, respectively), which was also comparable to the effects of telmisartan (-24.24/-31.90 mmHg, p<0.001). Plasma creatinine was not altered by any of the 3 drugs, however, renal fibrosis was significantly decreased by Bay 60-2770 (44.76%, p<0.05) and telmisartan (43.96%, p<0.05) versus placebo. On the other hand, BAY 41-8543 did not ameliorate renal fibrosis.
RNA-sequencing in renal tissues revealed that 144 genes were differentially regulated among the groups. Interestingly, 23 genes including collagen type VI alpha 5 (Col6a5), phospholipase C Eta 1 (Plch1) and claudin 19 (Cldn19) were exclusively differentially regulated by BAY 60-2770 and these genes might explain anti-fibrotic renal effects.
Conclusion
Only the sGC activator BAY60-2770 ameliorated renal fibrosis comparable to the gold-standard treatment of CKD with an ARB (telmisartan). These effects were blood pressure independent since blood pressure was similar in all treatment groups. Inactivation of the sGC by oxidative stress in our CKD model may explain the failure of the sGC stimulator in reducing kidney fibrosis. The mechanisms underlying the renal anti-fibrotic effects of BAY60-2770 might involve the differential regulation of Col6a5, Plch1 and Cldn19.