Abstract
Chronic kidney diseaQueryse (CKD) is associated with oxidative stress which can interrupt the nitric oxide (NO)/soluble guanylyl cyclase (sGC) signaling and decrease cyclic guanosine monophosphate (cGMP) production. Low cGMP concentrations can cause kidney damage and progression of CKD. The novel sGC activator runcaciguat targets the oxidized and heme-free form of sGC, restoring cGMP production under oxidative stress. The purpose of this study is to investigate if runcaciguat could provide an effective treatment for CKD. Runcaciguat was used for the treatment not only in rat CKD models with different etiologies and comorbidities, namely of hypertensive rats, the renin transgenic (RenTG) rat, and angiotensin-supplemented (ANG-SD) rat, but also in rats with diabetic and metabolic CKD, the Zucker diabetic fatty (ZDF) rat. The treatment duration was 2 to 42 weeks and runcaciguat was applied orally in doses from 1 to 10 mg/kg/bid. In these different rat CKD models, runcaciguat significantly reduced proteinuria (urinary protein to creatinine ratio; uPCR). These effects were also significant at doses which did not or only moderately decrease systemic blood pressure. Moreover, runcaciguat significantly decreased kidney injury biomarkers and attenuated morphological kidney damages. In RenTG rats, runcaciguat improved survival rates and markers of heart injury. These data demonstrate that the sGC activator runcaciguat exhibits cardio-renal protection at doses which did not reduce blood pressure and was effective in hypertensive as well as diabetic and metabolic CKD models. These data, therefore, suggest that runcaciguat, with its specific mode of action, represents an efficient treatment approach for CKD and associated CV diseases.Graphical abstract
Highlights
The nitric oxide (NO), soluble guanylyl cyclase, cyclic guanosine 3′,5′-monophosphate signaling cascade (NO-sGC-cGMP pathway), is a pivotal signaling pathway that regulates many cells, tissues, and organ functions
Our results suggest that the novel NO- and heme-independent sGC activator runcaciguat could significantly attenuate or even stop further renal deterioration in these models and leads to a reduced overall mortality
The effects of runcaciguat were investigated in a model of hypertension-driven kidney damage with progressive proteinuria
Summary
The nitric oxide (NO), soluble guanylyl cyclase (sGC), cyclic guanosine 3′,5′-monophosphate (cGMP) signaling cascade (NO-sGC-cGMP pathway), is a pivotal signaling pathway that regulates many cells, tissues, and organ functions. It has been shown that cGMP is a prominent regulator of kidney function and could be involved in the regulation of cortical renal blood flow of afferent and efferent arterioles and of medullary perfusion. Common comorbidities in cardiovascular and kidney disease like hypertension, diabetes, or obesity are leading to endothelial dysfunction and the impairment of cGMP production which can cause a progressive damage of blood vessels and trigger end-organ damage in the heart and the kidney. This can result in chronic kidney disease (CKD) and end-stage renal disease (ESRD)
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