Discovery of RXFP2 genetic association in resistant hypertensive men and RXFP2 antagonists for the treatment of resistant hypertension
Abstract Hypertension remains a leading cause of cardiovascular and kidney diseases. Failure to control blood pressure with ≥ 3 medications or control requiring ≥ 4 medications is classified as resistant hypertension (rHTN) and new therapies are needed to reduce the resulting increased risk of morbi...
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Nature Portfolio
2024-06-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-62804-7 |
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| author | Shan-Shan Zhang Lance Larrabee Andrew H. Chang Sapna Desai Lisa Sloan Xin Wang Yixuan Wu Nazia Parvez Karen Amaratunga Allison C. Hartman Abby Whitnall Joseph Mason Nicholas P. Barton Audrey Y. Chu Jonathan M. Davitte Adam J. Csakai Caitlin Vestal Tibbetts Audrey E. Tolbert Heather O’Keefe Jessie Polanco Joseph Foley Casey Kmett Jonathan Kehler Gabriela Kozejova Feng Wang Andrew P. Mayer Patrick Koenig Davide Foletti Steven J. Pitts Christine G. Schnackenberg |
| author_facet | Shan-Shan Zhang Lance Larrabee Andrew H. Chang Sapna Desai Lisa Sloan Xin Wang Yixuan Wu Nazia Parvez Karen Amaratunga Allison C. Hartman Abby Whitnall Joseph Mason Nicholas P. Barton Audrey Y. Chu Jonathan M. Davitte Adam J. Csakai Caitlin Vestal Tibbetts Audrey E. Tolbert Heather O’Keefe Jessie Polanco Joseph Foley Casey Kmett Jonathan Kehler Gabriela Kozejova Feng Wang Andrew P. Mayer Patrick Koenig Davide Foletti Steven J. Pitts Christine G. Schnackenberg |
| author_sort | Shan-Shan Zhang |
| collection | DOAJ |
| description | Abstract Hypertension remains a leading cause of cardiovascular and kidney diseases. Failure to control blood pressure with ≥ 3 medications or control requiring ≥ 4 medications is classified as resistant hypertension (rHTN) and new therapies are needed to reduce the resulting increased risk of morbidity and mortality. Here, we report genetic evidence that relaxin family peptide receptor 2 (RXFP2) is associated with rHTN in men, but not in women. This study shows that adrenal gland gene expression of RXFP2 is increased in men with hypertension and the RXFP2 natural ligand, INSL3, increases adrenal steroidogenesis and corticosteroid secretion in human adrenal cells. To address the hypothesis that RXFP2 activation is an important mechanism in rHTN, we discovered and characterized small molecule and monoclonal antibody (mAb) blockers of RXFP2. The novel chemical entities and mAbs show potent, selective inhibition of RXFP2 and reduce aldosterone and cortisol synthesis and release. The RXFP2 mAbs have suitable rat pharmacokinetic profiles to evaluate the role of RXFP2 in the development and maintenance of rHTN. Overall, we identified RXFP2 activity as a potential new mechanism in rHTN and discovered RXFP2 antagonists for the future interrogation of RXFP2 in cardiovascular and renal diseases. |
| format | Article |
| id | doaj-art-c1b96aec0fcd4bf58710e7f61b920681 |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-c1b96aec0fcd4bf58710e7f61b9206812025-08-20T02:59:22ZengNature PortfolioScientific Reports2045-23222024-06-0114112010.1038/s41598-024-62804-7Discovery of RXFP2 genetic association in resistant hypertensive men and RXFP2 antagonists for the treatment of resistant hypertensionShan-Shan Zhang0Lance Larrabee1Andrew H. Chang2Sapna Desai3Lisa Sloan4Xin Wang5Yixuan Wu6Nazia Parvez7Karen Amaratunga8Allison C. Hartman9Abby Whitnall10Joseph Mason11Nicholas P. Barton12Audrey Y. Chu13Jonathan M. Davitte14Adam J. Csakai15Caitlin Vestal Tibbetts16Audrey E. Tolbert17Heather O’Keefe18Jessie Polanco19Joseph Foley20Casey Kmett21Jonathan Kehler22Gabriela Kozejova23Feng Wang24Andrew P. Mayer25Patrick Koenig26Davide Foletti27Steven J. Pitts28Christine G. Schnackenberg29Therapeutics Division, 23andMeTherapeutics Division, 23andMeTherapeutics Division, 23andMeMedicinal Science and Technology, GSK, Medicines Research CentreMedicinal Science and Technology, GSK, Medicines Research CentreResearch, 23andMeTherapeutics Division, 23andMeMedicinal Science and Technology, GSK, Medicines Research CentreMedicinal Science and Technology, GSK, Medicines Research CentreMedicinal Science and Technology, GSKMedicinal Science and Technology, GSK, Medicines Research CentreMedicinal Science and Technology, GSK, Medicines Research CentreMedicinal Science and Technology, GSK, Medicines Research CentreGenomic Sciences, GSKGenomic Sciences, GSKMedicinal Science and Technology, GSKMedicinal Science and Technology, GSKMedicinal Science and Technology, GSKMedicinal Science and Technology, GSKTherapeutics Division, 23andMeNovel Human Genetics Research Unit, GSKDMPK, GSKBioanalysis, Immunogenicity and Biomarkers, GSKMedicinal Science and Technology, GSK, Medicines Research CentreDMPK, GSKBioanalysis, Immunogenicity and Biomarkers, GSKTherapeutics Division, 23andMeTherapeutics Division, 23andMeResearch, 23andMeNovel Human Genetics Research Unit, GSKAbstract Hypertension remains a leading cause of cardiovascular and kidney diseases. Failure to control blood pressure with ≥ 3 medications or control requiring ≥ 4 medications is classified as resistant hypertension (rHTN) and new therapies are needed to reduce the resulting increased risk of morbidity and mortality. Here, we report genetic evidence that relaxin family peptide receptor 2 (RXFP2) is associated with rHTN in men, but not in women. This study shows that adrenal gland gene expression of RXFP2 is increased in men with hypertension and the RXFP2 natural ligand, INSL3, increases adrenal steroidogenesis and corticosteroid secretion in human adrenal cells. To address the hypothesis that RXFP2 activation is an important mechanism in rHTN, we discovered and characterized small molecule and monoclonal antibody (mAb) blockers of RXFP2. The novel chemical entities and mAbs show potent, selective inhibition of RXFP2 and reduce aldosterone and cortisol synthesis and release. The RXFP2 mAbs have suitable rat pharmacokinetic profiles to evaluate the role of RXFP2 in the development and maintenance of rHTN. Overall, we identified RXFP2 activity as a potential new mechanism in rHTN and discovered RXFP2 antagonists for the future interrogation of RXFP2 in cardiovascular and renal diseases.https://doi.org/10.1038/s41598-024-62804-7 |
| spellingShingle | Shan-Shan Zhang Lance Larrabee Andrew H. Chang Sapna Desai Lisa Sloan Xin Wang Yixuan Wu Nazia Parvez Karen Amaratunga Allison C. Hartman Abby Whitnall Joseph Mason Nicholas P. Barton Audrey Y. Chu Jonathan M. Davitte Adam J. Csakai Caitlin Vestal Tibbetts Audrey E. Tolbert Heather O’Keefe Jessie Polanco Joseph Foley Casey Kmett Jonathan Kehler Gabriela Kozejova Feng Wang Andrew P. Mayer Patrick Koenig Davide Foletti Steven J. Pitts Christine G. Schnackenberg Discovery of RXFP2 genetic association in resistant hypertensive men and RXFP2 antagonists for the treatment of resistant hypertension Scientific Reports |
| title | Discovery of RXFP2 genetic association in resistant hypertensive men and RXFP2 antagonists for the treatment of resistant hypertension |
| title_full | Discovery of RXFP2 genetic association in resistant hypertensive men and RXFP2 antagonists for the treatment of resistant hypertension |
| title_fullStr | Discovery of RXFP2 genetic association in resistant hypertensive men and RXFP2 antagonists for the treatment of resistant hypertension |
| title_full_unstemmed | Discovery of RXFP2 genetic association in resistant hypertensive men and RXFP2 antagonists for the treatment of resistant hypertension |
| title_short | Discovery of RXFP2 genetic association in resistant hypertensive men and RXFP2 antagonists for the treatment of resistant hypertension |
| title_sort | discovery of rxfp2 genetic association in resistant hypertensive men and rxfp2 antagonists for the treatment of resistant hypertension |
| url | https://doi.org/10.1038/s41598-024-62804-7 |
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