The Renoprotective Effects of the Soluble Guanylate Cyclase (sGC) Activator Runcaciguat Are Associated with Distinct Changes in Renal Gene Expression Profiles

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Background: Chronic kidney disease (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, thereby, restores cGMP signaling. In the ZSF-1 rat CKD-model, runcaciguat displays renoprotective effects (pronounced decrease in proteinuria and lowering of HbA1c and triglycerides). To understand the underlying mode of action of the renoprotective and metabolic effects of runcaciguat, we investigated the renal gene expression profile. Methods: The renal expression profile of genes affected by 3mg/kg/bid runcaciguat in obese ZSF1 rats treated between 16 to 27 weeks of age was analyzed with a microarray (all known rat genes) and compared to gene expression changes of lean relative to obese ZSF1 rats aged 14 to 26 weeks to show deregulation over the course of the disease progression. Results: With the selected deregulation thresholds, 45 and 82 genes were expressed at higher and lower levels after runcaciguat treatment, respectively. Thresholds were set as 1.6-fold differences between vehicle and treatment group with p<0.05. Most of the genes decreased by runcaciguat also show decreased expression in lean vs. obese ZSF1 rat kidney, suggesting that runcaciguat converts the kidney expression profile of obese ZSF1 rats partly to the lean pattern. Most of these genes encode proteins involved in fibrosis (e.g. collagens), inflammation (e.g. cytokines), and degeneration/regeneration (e.g. cell cycle progression genes, lipocalin 2) which is supported by the Ingenuity pathway analysis (IPA) Conclusions: The runcaciguat-induced gene expression changes clearly indicate an at least partial reversal of the fibrotic phenotype and enhanced vascular-endothelial functions in the ZSF-1 CKD rat model. These changes could contribute to the renoprotective effect of runcaciguat. Runcaciguat is currently evaluated in a Ph2a clinical trial (CONCORD) for CKD. Funding: Commercial Support - Bayer AG

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