PMID- 34948014 OWN - NLM STAT- MEDLINE DCOM- 20220131 LR - 20220131 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 22 IP - 24 DP - 2021 Dec 8 TI - Salt-Sensitive Hypertension in GR(+/-) Rats Is Accompanied with Dysregulation in Adrenal Soluble Epoxide Hydrolase and Polyunsaturated Fatty Acid Pathways. LID - 10.3390/ijms222413218 [doi] LID - 13218 AB - Mutations within the glucocorticoid receptor (GR) gene locus lead to glucocorticoid resistance which is characterized by several clinical symptoms such as adrenal gland hyperplasia and salt-sensitive hypertension, although the underlying mechanisms are still unknown. We studied GR haploinsufficient (GR(+/-)) Sprague Dawley rats which, on a standard diet, showed significantly increased plasma aldosterone and corticosterone levels and an adrenocortex hyperplasia accompanied by a normal systolic blood pressure. Following a high salt diet, these rats developed salt-sensitive hypertension and maintained elevated enzyme-soluble epoxide hydrolase (sEH) in adrenal glands, while sEH was significantly decreased in wild-type rats. Furthermore, GR(+/-) rats showed dysregulation of the equilibrated linoleic and arachidonic acid pathways, with a significant increase of less active metabolites such as 8,9-DiHETrE. In Sprague Dawley rats, GR haploinsufficiency induced steroid disturbances, which provoked hypertension only in combination with high salt intake, which was accompanied by disturbances in sEH and fatty acid metabolism. Our results suggest that sEH inhibition could be a potential target to treat hypertension in patients with GR haploinsufficiency. FAU - Vanderriele, Paul-Emmanuel AU - Vanderriele PE AD - Department of Biomedical Science, University of Lausanne, 1015 Lausanne, Switzerland. AD - National Center of Competence in Research Kidney.CH, 8057 Zurich, Switzerland. FAU - Wang, Qing AU - Wang Q AD - Division of Nephrology and Hypertension, Lausanne University Hospital (CHUV), 1015 Lausanne, Switzerland. FAU - Merillat, Anne-Marie AU - Merillat AM AD - Department of Biomedical Science, University of Lausanne, 1015 Lausanne, Switzerland. FAU - Ino, Frederique AU - Ino F AD - Department of Biomedical Science, University of Lausanne, 1015 Lausanne, Switzerland. FAU - Aeschlimann, Gilles AU - Aeschlimann G AD - Department of Biomedical Science, University of Lausanne, 1015 Lausanne, Switzerland. FAU - Ehret, Xavier AU - Ehret X AD - Department of Biomedical Science, University of Lausanne, 1015 Lausanne, Switzerland. FAU - Ancin Del Olmo, David AU - Ancin Del Olmo D AD - Department of Biomedical Science, University of Lausanne, 1015 Lausanne, Switzerland. FAU - Ponce de Leon, Veronica AU - Ponce de Leon V AD - Department of Biomedical Science, University of Lausanne, 1015 Lausanne, Switzerland. AD - National Center of Competence in Research Kidney.CH, 8057 Zurich, Switzerland. FAU - Scholl, Ute I AU - Scholl UI AD - Department of Nephrology, School of Medicine, Heinrich-Heine-Universitat Dusseldorf, 40225 Dusseldorf, Germany. AD - Center of Functional Genomics, Berlin Institute of Health at Charite, Universitatsmedizin Berlin, 10117 Berlin, Germany. FAU - Winter, Denise V AU - Winter DV AD - National Center of Competence in Research Kidney.CH, 8057 Zurich, Switzerland. AD - Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland. FAU - Odermatt, Alex AU - Odermatt A AUID- ORCID: 0000-0002-6820-2712 AD - National Center of Competence in Research Kidney.CH, 8057 Zurich, Switzerland. AD - Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland. FAU - Hummler, Edith AU - Hummler E AD - Department of Biomedical Science, University of Lausanne, 1015 Lausanne, Switzerland. AD - National Center of Competence in Research Kidney.CH, 8057 Zurich, Switzerland. FAU - Verouti, Sophia N AU - Verouti SN AUID- ORCID: 0000-0002-2297-2738 AD - Department of Biomedical Science, University of Lausanne, 1015 Lausanne, Switzerland. AD - National Center of Competence in Research Kidney.CH, 8057 Zurich, Switzerland. LA - eng GR - 31003A-182478/1/SNSF_/Swiss National Science Foundation/Switzerland GR - N-403-07-23/National Center of Competence in Research (NCCR)/ PT - Journal Article DEP - 20211208 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Fatty Acids, Unsaturated) RN - 0 (Receptors, Glucocorticoid) RN - 0 (Sodium Chloride, Dietary) RN - 4964P6T9RB (Aldosterone) RN - EC 3.3.2.- (Epoxide Hydrolases) RN - W980KJ009P (Corticosterone) SB - IM MH - Adrenal Glands/enzymology/*pathology MH - Aldosterone/blood MH - Animals MH - Corticosterone/blood MH - Epoxide Hydrolases/*metabolism MH - Fatty Acids, Unsaturated MH - Haploinsufficiency MH - Hyperplasia MH - Hypertension/chemically induced/genetics/*metabolism MH - Male MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, Glucocorticoid/*genetics MH - Signal Transduction MH - Sodium Chloride, Dietary/*adverse effects PMC - PMC8708190 OTO - NOTNLM OT - Chrousos syndrome OT - adrenal gland hyperplasia OT - glucocorticoid receptor OT - glucocorticoid resistance OT - hypertension OT - soluble-epoxide hydrolase COIS- The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. EDAT- 2021/12/25 06:00 MHDA- 2022/02/01 06:00 PMCR- 2021/12/08 CRDT- 2021/12/24 01:16 PHST- 2021/11/02 00:00 [received] PHST- 2021/12/01 00:00 [revised] PHST- 2021/12/03 00:00 [accepted] PHST- 2021/12/24 01:16 [entrez] PHST- 2021/12/25 06:00 [pubmed] PHST- 2022/02/01 06:00 [medline] PHST- 2021/12/08 00:00 [pmc-release] AID - ijms222413218 [pii] AID - ijms-22-13218 [pii] AID - 10.3390/ijms222413218 [doi] PST - epublish SO - Int J Mol Sci. 2021 Dec 8;22(24):13218. doi: 10.3390/ijms222413218.