Effects of Two Soluble ACE2-Fc Variants on Blood Pressure and Albuminuria in Hypertensive Mice: Research Letter
Background: Angiotensin-converting enzyme 2 (ACE2) hydrolyzes angiotensin (Ang) II to Ang-(1-7), promoting vasodilatation, and inhibiting oxidative stress and inflammation. Plasma membrane ACE2 is the receptor for all known SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) viral variants....
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
SAGE Publishing
2023-10-01
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| Series: | Canadian Journal of Kidney Health and Disease |
| Online Access: | https://doi.org/10.1177/20543581231207146 |
| _version_ | 1797652403885965312 |
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| author | Mayra Trentin-Sonoda Joseph Zimpelmann Karishma Tailor John W. Gillard Nathan Yoganathan Traian Sulea Kevin D. Burns |
| author_facet | Mayra Trentin-Sonoda Joseph Zimpelmann Karishma Tailor John W. Gillard Nathan Yoganathan Traian Sulea Kevin D. Burns |
| author_sort | Mayra Trentin-Sonoda |
| collection | DOAJ |
| description | Background: Angiotensin-converting enzyme 2 (ACE2) hydrolyzes angiotensin (Ang) II to Ang-(1-7), promoting vasodilatation, and inhibiting oxidative stress and inflammation. Plasma membrane ACE2 is the receptor for all known SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) viral variants. In COVID-19 infection, soluble ACE2 variants may act as decoys to bind and neutralize the coronavirus, reducing its tissue infectivity. Furthermore, soluble ACE2 variants have been proposed as potential therapeutics for kidney disease and hypertensive disorders. Objective: Soluble ACE2 variants conjugated to human Fc domains and selected for high-potency viral SARS-CoV-2 neutralization were prepared and evaluated for ACE2 activity in vitro. Lead candidates were then tested for systemic ACE2 activity, stability, and effects on blood pressure and albuminuria in mice with Ang II-induced hypertension. Methods: ACE2 activity of 10 soluble ACE2 variants was first assessed in cell-free conditions using a fluorogenic substrate, or by Ang II hydrolysis to Ang-(1-7). Hypertension was induced in male or female mice by implantation of osmotic minipumps containing Ang II. Two lead ACE2 variants were injected intravenously (i.v.) into hypertensive mice, followed by measurements of blood pressure (tail-cuff plethysmography), albuminuria, and tissue ACE2 activity and protein (immunoblots). Results: Soluble ACE2-Fc variants demonstrated significant ACE2 enzymatic activity, with kinetics comparable with human recombinant ACE2. In hypertensive mice, single dose i.v. injection of ACE2-Fc variant K (10 mg/kg) significantly decreased systolic blood pressure at 24 hours, with partial lowering sustained to 48 hours, and tendency to reduce albuminuria at 72 hours. By contrast, ACE2-Fc variant I had no effect on blood pressure or albuminuria in hypertensive mice; ACE2-Fc variant K was detected by immunoblotting in plasma, kidney, heart, lung, liver, and spleen lysates 72 hours after injection, associated with significantly increased ACE2 activity in all tissues except kidney and spleen. Angiotensin-converting enzyme 2-Fc variant I had no effect on plasma ACE2 activity. Conclusions: Soluble ACE2-Fc variant K reduces blood pressure and tends to lower albuminuria in hypertensive mice. Furthermore, soluble ACE2-Fc variant K has prolonged tissue retention, associated with increased tissue ACE2 activity. The results support further studies directed at the therapeutic potential of soluble ACE2-Fc variant K for cardiovascular and kidney protection. |
| first_indexed | 2024-03-11T16:29:28Z |
| format | Article |
| id | doaj.art-ad4d0e9cf9494a689a3481920aa10e84 |
| institution | Directory Open Access Journal |
| issn | 2054-3581 |
| language | English |
| last_indexed | 2024-03-11T16:29:28Z |
| publishDate | 2023-10-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Canadian Journal of Kidney Health and Disease |
| spelling | doaj.art-ad4d0e9cf9494a689a3481920aa10e842023-10-24T09:03:41ZengSAGE PublishingCanadian Journal of Kidney Health and Disease2054-35812023-10-011010.1177/20543581231207146Effects of Two Soluble ACE2-Fc Variants on Blood Pressure and Albuminuria in Hypertensive Mice: Research LetterMayra Trentin-Sonoda0Joseph Zimpelmann1Karishma Tailor2John W. Gillard3Nathan Yoganathan4Traian Sulea5Kevin D. Burns6Division of Nephrology, Department of Medicine, Kidney Research Centre, The Ottawa Hospital Research Institute, University of Ottawa, ON, CanadaDivision of Nephrology, Department of Medicine, Kidney Research Centre, The Ottawa Hospital Research Institute, University of Ottawa, ON, CanadaDivision of Nephrology, Department of Medicine, Kidney Research Centre, The Ottawa Hospital Research Institute, University of Ottawa, ON, CanadaJN Nova Pharma Inc., Montreal, QC, CanadaJN Nova Pharma Inc., Montreal, QC, CanadaHuman Health Therapeutics Research Centre, National Research Council Canada, Montreal, QC, CanadaDivision of Nephrology, Department of Medicine, Kidney Research Centre, The Ottawa Hospital Research Institute, University of Ottawa, ON, CanadaBackground: Angiotensin-converting enzyme 2 (ACE2) hydrolyzes angiotensin (Ang) II to Ang-(1-7), promoting vasodilatation, and inhibiting oxidative stress and inflammation. Plasma membrane ACE2 is the receptor for all known SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) viral variants. In COVID-19 infection, soluble ACE2 variants may act as decoys to bind and neutralize the coronavirus, reducing its tissue infectivity. Furthermore, soluble ACE2 variants have been proposed as potential therapeutics for kidney disease and hypertensive disorders. Objective: Soluble ACE2 variants conjugated to human Fc domains and selected for high-potency viral SARS-CoV-2 neutralization were prepared and evaluated for ACE2 activity in vitro. Lead candidates were then tested for systemic ACE2 activity, stability, and effects on blood pressure and albuminuria in mice with Ang II-induced hypertension. Methods: ACE2 activity of 10 soluble ACE2 variants was first assessed in cell-free conditions using a fluorogenic substrate, or by Ang II hydrolysis to Ang-(1-7). Hypertension was induced in male or female mice by implantation of osmotic minipumps containing Ang II. Two lead ACE2 variants were injected intravenously (i.v.) into hypertensive mice, followed by measurements of blood pressure (tail-cuff plethysmography), albuminuria, and tissue ACE2 activity and protein (immunoblots). Results: Soluble ACE2-Fc variants demonstrated significant ACE2 enzymatic activity, with kinetics comparable with human recombinant ACE2. In hypertensive mice, single dose i.v. injection of ACE2-Fc variant K (10 mg/kg) significantly decreased systolic blood pressure at 24 hours, with partial lowering sustained to 48 hours, and tendency to reduce albuminuria at 72 hours. By contrast, ACE2-Fc variant I had no effect on blood pressure or albuminuria in hypertensive mice; ACE2-Fc variant K was detected by immunoblotting in plasma, kidney, heart, lung, liver, and spleen lysates 72 hours after injection, associated with significantly increased ACE2 activity in all tissues except kidney and spleen. Angiotensin-converting enzyme 2-Fc variant I had no effect on plasma ACE2 activity. Conclusions: Soluble ACE2-Fc variant K reduces blood pressure and tends to lower albuminuria in hypertensive mice. Furthermore, soluble ACE2-Fc variant K has prolonged tissue retention, associated with increased tissue ACE2 activity. The results support further studies directed at the therapeutic potential of soluble ACE2-Fc variant K for cardiovascular and kidney protection.https://doi.org/10.1177/20543581231207146 |
| spellingShingle | Mayra Trentin-Sonoda Joseph Zimpelmann Karishma Tailor John W. Gillard Nathan Yoganathan Traian Sulea Kevin D. Burns Effects of Two Soluble ACE2-Fc Variants on Blood Pressure and Albuminuria in Hypertensive Mice: Research Letter Canadian Journal of Kidney Health and Disease |
| title | Effects of Two Soluble ACE2-Fc Variants on Blood Pressure and Albuminuria in Hypertensive Mice: Research Letter |
| title_full | Effects of Two Soluble ACE2-Fc Variants on Blood Pressure and Albuminuria in Hypertensive Mice: Research Letter |
| title_fullStr | Effects of Two Soluble ACE2-Fc Variants on Blood Pressure and Albuminuria in Hypertensive Mice: Research Letter |
| title_full_unstemmed | Effects of Two Soluble ACE2-Fc Variants on Blood Pressure and Albuminuria in Hypertensive Mice: Research Letter |
| title_short | Effects of Two Soluble ACE2-Fc Variants on Blood Pressure and Albuminuria in Hypertensive Mice: Research Letter |
| title_sort | effects of two soluble ace2 fc variants on blood pressure and albuminuria in hypertensive mice research letter |
| url | https://doi.org/10.1177/20543581231207146 |
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