Runcaciguat, a novel soluble guanylate cyclase activator, shows renoprotection in hypertensive, diabetic, and metabolic preclinical models of chronic kidney disease

• DOI: 10.1007/s00210-021-02149-4
• Publication Date: 2021-09-22T05:02:30Z
• Authors: Agnès Bénardeau; Antje Kahnert; Tibor Schomber; Jutta Meyer; Mira Pavkovic; Axel Kretschmer; Bettina Lawrenz; Elke Hartmann; Ilka Mathar; Joerg Hueser; Jan R. Kraehling; Frank Eitner; Michael G. Hahn; Johannes-Peter St...; Peter Sandner
• Keywords: Male; Cyclopropanes; 0301 basic medicine; 0303 health sciences; Time Factors; Dose-Response Relationship, Drug; Enzyme Activators; Blood Pressure; Rats; Diabetes Mellitus, Experimental; Rats, Zucker; 3. Good health; Rats, Sprague-Dawley; Disease Models, Animal; 03 medical and health sciences; Soluble Guanylyl Cyclase; Hypertension; Animals; Original Article; Rats, Transgenic; Renal Insufficiency, Chronic; Cyclic GMP

AbstractChronic 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