Runcaciguat, a novel soluble guanylate cyclase activator, shows renoprotection in hypertensive, diabetic, and metabolic preclinical models of chronic kidney disease.
Animals
Male
Rats
Blood Pressure
/ drug effects
Cyclic GMP
/ metabolism
Diabetes Mellitus, Experimental
/ complications
Disease Models, Animal
Dose-Response Relationship, Drug
Enzyme Activators
/ administration & dosage
Hypertension
/ complications
Rats, Sprague-Dawley
Rats, Transgenic
Rats, Zucker
Renal Insufficiency, Chronic
/ etiology
Soluble Guanylyl Cyclase
/ drug effects
Time Factors
Cyclopropanes
/ pharmacology
CKD
DKD
Runcaciguat
cGMP
sGC activator
Journal
Naunyn-Schmiedeberg's archives of pharmacology
ISSN: 1432-1912
Titre abrégé: Naunyn Schmiedebergs Arch Pharmacol
Pays: Germany
ID NLM: 0326264
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
09
08
2021
accepted:
31
08
2021
pubmed:
23
9
2021
medline:
16
2
2022
entrez:
22
9
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34550407
doi: 10.1007/s00210-021-02149-4
pii: 10.1007/s00210-021-02149-4
pmc: PMC8592982
doi:
Substances chimiques
Cyclic GMP
H2D2X058MU
Enzyme Activators
0
Soluble Guanylyl Cyclase
EC 4.6.1.2
BAY 1101042
0
Cyclopropanes
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2363-2379Informations de copyright
© 2021. The Author(s).
Références
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