Runcaciguat, a novel soluble guanylate cyclase activator, shows renoprotection in hypertensive, diabetic, and metabolic preclinical models of chronic kidney disease
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 sG...
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| creator | Bénardeau, Agnès Kahnert, Antje Schomber, Tibor Meyer, Jutta Pavkovic, Mira Kretschmer, Axel Lawrenz, Bettina Hartmann, Elke Mathar, Ilka Hueser, Joerg Kraehling, Jan R. Eitner, Frank Hahn, Michael G. Stasch, Johannes-Peter Sandner, Peter |
| description | 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 |
| doi_str_mv | 10.1007/s00210-021-02149-4 |
| format | Article |
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Graphical abstract</description><identifier>ISSN: 0028-1298</identifier><identifier>EISSN: 1432-1912</identifier><identifier>DOI: 10.1007/s00210-021-02149-4</identifier><identifier>PMID: 34550407</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Angiotensin ; Animal models ; Animals ; Biomedical and Life Sciences ; Biomedicine ; Blood pressure ; Blood Pressure - drug effects ; Creatinine ; Cyclic GMP ; Cyclic GMP - metabolism ; Cyclopropanes - pharmacology ; Cyclopropanes - therapeutic use ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Experimental - complications ; Diabetes Mellitus, Experimental - drug therapy ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Enzyme Activators - administration & dosage ; Enzyme Activators - pharmacology ; Guanylate cyclase ; Heme ; Hypertension ; Hypertension - complications ; Hypertension - drug therapy ; Kidney diseases ; Male ; Metabolism ; Neurosciences ; Nitric oxide ; Original ; Original Article ; Oxidative stress ; Pharmacology/Toxicology ; Proteinuria ; Rats ; Rats, Sprague-Dawley ; Rats, Transgenic ; Rats, Zucker ; Renal Insufficiency, Chronic - etiology ; Renal Insufficiency, Chronic - prevention & control ; Renin ; Soluble Guanylyl Cyclase - drug effects ; Soluble Guanylyl Cyclase - metabolism ; Time Factors</subject><ispartof>Naunyn-Schmiedeberg's archives of pharmacology, 2021-12, Vol.394 (12), p.2363-2379</ispartof><rights>The Author(s) 2021</rights><rights>2021. The Author(s).</rights><rights>The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-e80b55a2daef7b845390f80e9d974a8086621fca944443f1e20e6c575d9f46343</citedby><cites>FETCH-LOGICAL-c474t-e80b55a2daef7b845390f80e9d974a8086621fca944443f1e20e6c575d9f46343</cites><orcidid>0000-0003-2977-7553</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00210-021-02149-4$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00210-021-02149-4$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,27923,27924,41487,42556,51318</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34550407$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bénardeau, Agnès</creatorcontrib><creatorcontrib>Kahnert, Antje</creatorcontrib><creatorcontrib>Schomber, Tibor</creatorcontrib><creatorcontrib>Meyer, Jutta</creatorcontrib><creatorcontrib>Pavkovic, Mira</creatorcontrib><creatorcontrib>Kretschmer, Axel</creatorcontrib><creatorcontrib>Lawrenz, Bettina</creatorcontrib><creatorcontrib>Hartmann, Elke</creatorcontrib><creatorcontrib>Mathar, Ilka</creatorcontrib><creatorcontrib>Hueser, Joerg</creatorcontrib><creatorcontrib>Kraehling, Jan R.</creatorcontrib><creatorcontrib>Eitner, Frank</creatorcontrib><creatorcontrib>Hahn, Michael G.</creatorcontrib><creatorcontrib>Stasch, Johannes-Peter</creatorcontrib><creatorcontrib>Sandner, Peter</creatorcontrib><title>Runcaciguat, a novel soluble guanylate cyclase activator, shows renoprotection in hypertensive, diabetic, and metabolic preclinical models of chronic kidney disease</title><title>Naunyn-Schmiedeberg's archives of pharmacology</title><addtitle>Naunyn-Schmiedeberg's Arch Pharmacol</addtitle><addtitle>Naunyn Schmiedebergs Arch Pharmacol</addtitle><description>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</description><subject>Angiotensin</subject><subject>Animal models</subject><subject>Animals</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Blood pressure</subject><subject>Blood Pressure - drug effects</subject><subject>Creatinine</subject><subject>Cyclic GMP</subject><subject>Cyclic GMP - metabolism</subject><subject>Cyclopropanes - pharmacology</subject><subject>Cyclopropanes - therapeutic use</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Experimental - complications</subject><subject>Diabetes Mellitus, Experimental - drug therapy</subject><subject>Disease Models, Animal</subject><subject>Dose-Response Relationship, Drug</subject><subject>Enzyme Activators - administration & dosage</subject><subject>Enzyme Activators - pharmacology</subject><subject>Guanylate cyclase</subject><subject>Heme</subject><subject>Hypertension</subject><subject>Hypertension - complications</subject><subject>Hypertension - 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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</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>34550407</pmid><doi>10.1007/s00210-021-02149-4</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0003-2977-7553</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-1298 |
| ispartof | Naunyn-Schmiedeberg's archives of pharmacology, 2021-12, Vol.394 (12), p.2363-2379 |
| issn | 0028-1298 1432-1912 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8592982 |
| source | MEDLINE; SpringerLink Journals - AutoHoldings |
| subjects | Angiotensin Animal models Animals Biomedical and Life Sciences Biomedicine Blood pressure Blood Pressure - drug effects Creatinine Cyclic GMP Cyclic GMP - metabolism Cyclopropanes - pharmacology Cyclopropanes - therapeutic use Diabetes Diabetes mellitus Diabetes Mellitus, Experimental - complications Diabetes Mellitus, Experimental - drug therapy Disease Models, Animal Dose-Response Relationship, Drug Enzyme Activators - administration & dosage Enzyme Activators - pharmacology Guanylate cyclase Heme Hypertension Hypertension - complications Hypertension - drug therapy Kidney diseases Male Metabolism Neurosciences Nitric oxide Original Original Article Oxidative stress Pharmacology/Toxicology Proteinuria Rats Rats, Sprague-Dawley Rats, Transgenic Rats, Zucker Renal Insufficiency, Chronic - etiology Renal Insufficiency, Chronic - prevention & control Renin Soluble Guanylyl Cyclase - drug effects Soluble Guanylyl Cyclase - metabolism Time Factors |
| title | Runcaciguat, a novel soluble guanylate cyclase activator, shows renoprotection in hypertensive, diabetic, and metabolic preclinical models of chronic kidney disease |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-12T08%3A58%3A55IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Runcaciguat,%20a%20novel%20soluble%20guanylate%20cyclase%20activator,%20shows%20renoprotection%20in%20hypertensive,%20diabetic,%20and%20metabolic%20preclinical%20models%20of%20chronic%20kidney%20disease&rft.jtitle=Naunyn-Schmiedeberg's%20archives%20of%20pharmacology&rft.au=B%C3%A9nardeau,%20Agn%C3%A8s&rft.date=2021-12-01&rft.volume=394&rft.issue=12&rft.spage=2363&rft.epage=2379&rft.pages=2363-2379&rft.issn=0028-1298&rft.eissn=1432-1912&rft_id=info:doi/10.1007/s00210-021-02149-4&rft_dat=%3Cproquest_pubme%3E2597613334%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2597613334&rft_id=info:pmid/34550407&rfr_iscdi=true |