Abstract
Background Kidney fibrosis is frequently observed in cardiorenal diseases. Cyclic guanosine monophosphate (cGMP) serves as the most important second messenger of nitric oxide (NO) and has shown antifibrotic effects at enhanced levels in several experimental models of kidney diseases. Antifibrotic effects of cGMP signalling via cGMP-dependent protein kinases (cGK), in particular cGKI, have already been shown. Serelaxin and zaprinast are both able to increase cGMP signalling via influencing two independent pharmacological targets. Serelaxin is currently in phase III development for acute heart failure and has shown antifibrotic properties in several in vitro and in vivo experiments. It is discussed that serelaxin inhibits TGF-b signalling via RXFP1 receptor. Involvement of NO / cGMP in this process has also been revealed. Zaprinast is a selective inhibitor of phosphodiesterase V, which leads to enhanced levels of cGMP by blocking cGMP degradation.
Highlights
Kidney fibrosis is frequently observed in cardiorenal diseases
In wild type (WT), Serelaxin and Zaprinast significantly reduced renal interstitial fibrosis assessed by remodeling biomarkers, e.g. a-SMA, total collagen, Col1a1, fibronectin and gelatinases
In contrast to Zaprinast, Serelaxin showed no antifibrotic effects on mRNA and protein expression of extracellular matrix (ECM) accumulation in cGKI-KO. These results indicate that Serelaxin and Zaprinast have comparable antifibrotic effects in the kidney of WT animals
Summary
Differences in the renal antifibrotic signaling of serelaxin and zaprinast Veronika Wetzl1*, Lothar Faerber2, Franz Hofmann3, Elisabeth Schinner1, Jens Schlossmann1 Cyclic guanosine monophosphate (cGMP) serves as the most important second messenger of nitric oxide (NO) and has shown antifibrotic effects at enhanced levels in several experimental models of kidney diseases. Antifibrotic effects of cGMP signalling via cGMP-dependent protein kinases (cGK), in particular cGKI, have already been shown. Serelaxin and zaprinast are both able to increase cGMP signalling via influencing two independent pharmacological targets.
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