{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T13:54:13Z","timestamp":1785765253441,"version":"3.56.0"},"reference-count":46,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T00:00:00Z","timestamp":1785628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK125464"],"award-info":[{"award-number":["R01DK125464"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"award":["R01DK125464"],"award-info":[{"award-number":["R01DK125464"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Mineralocorticoid receptor (MR) blockade exerts sex-specific effects in hypertension and cardiovascular disease; however, its role in blood pressure regulation in spontaneously hypertensive rats (SHRs) remains unclear. We assessed the effects of MR antagonism on blood pressure and electrolyte balance in male and female SHRs aged 10\u201315 weeks. Higher serum K+ levels in spironolactone-treated female SHRs were accompanied by transiently reduced urinary K+ excretion and a fourfold increase in aldosterone at the study\u2019s end. These differences were not observed in male SHRs. Plasma renin activity and circulating corticosterone were 19% and 41% lower in females than in males but were unaffected by spironolactone in either sex. Plasma renin activity in SHRs was comparable to that of normotensive Wistar\u2013Kyoto rats. Females exhibited approximately twofold higher renal MR and 1.7-fold greater renal 11\u03b2-hydroxysteroid dehydrogenase type 2 (11\u03b2-HSD2) protein levels. MR antagonism did not alter ENaC activity, \u03b1-ENaC protein abundance, blood pressure, or amiloride-sensitive urinary electrolyte excretion in either sex. Collectively, the upregulation of renal MR and 11\u03b2-HSD2 in females was associated with elevated circulating potassium in response to MR blockade, an effect that was likely counterbalanced by a compensatory rise in aldosterone. Low renin\u2013angiotensin\u2013aldosterone system activity in SHRs may limit the antihypertensive efficacy of MR antagonists.<\/jats:p>","DOI":"10.3390\/ijms27156953","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T12:57:56Z","timestamp":1785761876000},"page":"6953","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Upregulated Renal Mineralocorticoid Receptor and 11\u03b2-Hydroxysteroid Dehydrogenase Type 2 Are Associated with K+ Retention During MR Antagonism in Female Spontaneously Hypertensive Rats"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4573-8466","authenticated-orcid":false,"given":"Irina","family":"Baranovskaya","sequence":"first","affiliation":[{"name":"Immunology Center of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iryna","family":"Bilous","sequence":"additional","affiliation":[{"name":"Department of Physiology, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sati","family":"Alexander","sequence":"additional","affiliation":[{"name":"Department of Physiology, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Tubalinal","sequence":"additional","affiliation":[{"name":"College of Allied Health Sciences, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alena","family":"Cherezova","sequence":"additional","affiliation":[{"name":"Department of Physiology, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vadym","family":"Buncha","sequence":"additional","affiliation":[{"name":"Department of Physiology & Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5248-5817","authenticated-orcid":false,"given":"Mikhail","family":"Fomin","sequence":"additional","affiliation":[{"name":"Immunology Center of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celso","family":"Gomez-Sanchez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8683-0715","authenticated-orcid":false,"given":"Mykola","family":"Mamenko","sequence":"additional","affiliation":[{"name":"Department of Physiology, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1056\/NEJM199909023411001","article-title":"The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators","volume":"341","author":"Pitt","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1056\/NEJMoa2025845","article-title":"Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes","volume":"383","author":"Bakris","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1161\/CIRCULATIONAHA.120.051898","article-title":"Finerenone and Cardiovascular Outcomes in Patients With Chronic Kidney Disease and Type 2 Diabetes","volume":"143","author":"Filippatos","year":"2021","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.ahj.2017.03.011","article-title":"True rate of mineralocorticoid receptor antagonists-related hyperkalemia in placebo-controlled trials: A meta-analysis","volume":"188","author":"Vukadinovic","year":"2017","journal-title":"Am. Heart J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1038\/nrneph.2012.217","article-title":"Management of hyperkalaemia consequent to mineralocorticoid-receptor antagonist therapy","volume":"8","author":"Roscioni","year":"2012","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1161\/HYPERTENSIONAHA.117.11087","article-title":"Biological Sex Modulates the Adrenal and Blood Pressure Responses to Angiotensin II","volume":"71","author":"Shukri","year":"2018","journal-title":"Hypertension"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s13293-019-0238-6","article-title":"Sex-specific responses to mineralocorticoid receptor antagonism in hypertensive African American males and females","volume":"10","author":"Clemmer","year":"2019","journal-title":"Biol. Sex. Differ."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2196","DOI":"10.1161\/HYPERTENSIONAHA.123.21287","article-title":"Aldosterone Antagonism Is More Effective at Reducing Blood Pressure and Excessive Renal ENaC Activity in AngII-Infused Female Rats Than in Males","volume":"80","author":"Buncha","year":"2023","journal-title":"Hypertension"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1161\/HYPERTENSIONAHA.118.11303","article-title":"Lack of Suppression of Aldosterone Production Leads to Salt-Sensitive Hypertension in Female but Not Male Balb\/C Mice","volume":"72","author":"Faulkner","year":"2018","journal-title":"Hypertension"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1161\/HYPERTENSIONAHA.115.06642","article-title":"Leptin Induces Hypertension and Endothelial Dysfunction via Aldosterone-Dependent Mechanisms in Obese Female Mice","volume":"67","author":"Huby","year":"2016","journal-title":"Hypertension"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e87","DOI":"10.1161\/HYP.0000000000000090","article-title":"Animal Models of Hypertension: A Scientific Statement From the American Heart Association","volume":"73","author":"Lerman","year":"2019","journal-title":"Hypertension"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"906327","DOI":"10.1155\/2012\/906327","article-title":"Association of aldosterone and cortisol with cardiovascular risk factors in prehypertension stage","volume":"2012","author":"Syed","year":"2012","journal-title":"Int. J. Hypertens."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"bvab146","DOI":"10.1210\/jendso\/bvab146","article-title":"11betaHSD2 Efficacy in Preventing Transcriptional Activation of the Mineralocorticoid Receptor by Corticosterone","volume":"5","author":"Ali","year":"2021","journal-title":"J. Endocr. Soc."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Ding, Y., Cheng, M., Cao, B., Liu, M., Hu, X., and Wu, D. (2024). Case report: Clinical characteristics and Genetical analysis of HSD11B2 in three Chinese children with apparent mineralocorticoid excess: A case series. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1491825"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1161\/HYPERTENSIONAHA.119.12802","article-title":"Progesterone Predisposes Females to Obesity-Associated Leptin-Mediated Endothelial Dysfunction via Upregulating Endothelial MR (Mineralocorticoid Receptor) Expression","volume":"74","author":"Faulkner","year":"2019","journal-title":"Hypertension"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1161\/HYPERTENSIONAHA.118.11014","article-title":"Age-Related Blood Pressure Sensitivity to Aldosterone in Blacks and Whites","volume":"72","author":"Tu","year":"2018","journal-title":"Hypertension"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1111\/j.1469-7793.1998.629bm.x","article-title":"Regulation of distal nephron K+ channels (ROMK) mRNA expression by aldosterone in rat kidney","volume":"509","author":"Beesley","year":"1998","journal-title":"J. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1016\/j.kint.2016.12.010","article-title":"The renal TRPV4 channel is essential for adaptation to increased dietary potassium","volume":"91","author":"Mamenko","year":"2017","journal-title":"Kidney Int."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"F463","DOI":"10.1152\/ajprenal.00171.2013","article-title":"Regulation of BK-alpha expression in the distal nephron by aldosterone and urine pH","volume":"305","author":"Wen","year":"2013","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"F748","DOI":"10.1152\/ajprenal.00655.2020","article-title":"Rapid development of vasopressin resistance in dietary K(+) deficiency","volume":"320","author":"Grimm","year":"2021","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S1550-8579(06)80193-2","article-title":"Estrogens contribute to a sex difference in plasma potassium concentration: A mechanism for regulation of adrenal angiotensin receptors","volume":"3","author":"Zheng","year":"2006","journal-title":"Gend. Med."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zietara, A., Dissanayake, L.V., Lowe, M., Xu, B., Levchenko, V., Kain, V., Halade, G.V., Klemens, C.A., Palygin, O., and Staruschenko, A. (2025). Potassium supplementation and depletion during development of salt-sensitive hypertension in male and female SS rats. JCI Insight, 10.","DOI":"10.1172\/jci.insight.181778"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1080\/07315724.2020.1765893","article-title":"Rising Trend of Hypokalemia Prevalence in the US Population and Possible Food Causes","volume":"40","author":"Sun","year":"2021","journal-title":"J. Am. Coll. Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.csbj.2023.11.044","article-title":"Sociodemographic and clinical factors influencing serum potassium concentration: A retrospective cohort study","volume":"24","author":"Wang","year":"2024","journal-title":"Comput Struct. Biotechnol. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1373\/49.1.190","article-title":"Sex and age differences in serum potassium in the United States","volume":"49","author":"Wysowski","year":"2003","journal-title":"Clin. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Al-Qusairi, L. (2026). Sex differences in potassium regulation: Evidence, molecular mechanisms and clinical implications. Biol. Sex. Differ., 17.","DOI":"10.1186\/s13293-026-00862-4"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1210\/jc.2005-1542","article-title":"The ectopic adrenocorticotropin syndrome: Clinical features, diagnosis, management, and long-term follow-up","volume":"91","author":"Isidori","year":"2006","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"13","DOI":"10.33549\/physiolres.932717","article-title":"Nifedipine-sensitive blood pressure component in hypertensive models characterized by high activity of either sympathetic nervous system or renin-angiotensin system","volume":"63","author":"Zicha","year":"2014","journal-title":"Physiol. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1093\/ajh\/7.2.193","article-title":"Vascular structural and functional alterations before and after the development of hypertension in SHR","volume":"7","author":"Rizzoni","year":"1994","journal-title":"Am. J. Hypertens."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1152\/ajplegacy.1976.231.4.1295","article-title":"Renin-angiotensin system in spontaneously hypertensive rats","volume":"231","author":"Shiono","year":"1976","journal-title":"Am. J. Physiol."},{"key":"ref_31","first-page":"435","article-title":"Blood pressure changes produced by kidney cross-transplantation between spontaneously hypertensive rats and normotensive rats","volume":"47","author":"Bianchi","year":"1974","journal-title":"Clin. Sci. Mol. Med."},{"key":"ref_32","first-page":"R175","article-title":"Kidneys from normotensive donors lower blood pressure in young transplanted spontaneously hypertensive rats","volume":"273","author":"Patschan","year":"1997","journal-title":"Am. J. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1210\/endo-109-6-1841","article-title":"The role of aldosterone in the development of hypertension in spontaneously hypertensive rats","volume":"109","author":"Kenyon","year":"1981","journal-title":"Endocrinology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"F957","DOI":"10.1152\/ajprenal.00413.2004","article-title":"Increased expression of ENaC subunits and increased apical targeting of AQP2 in the kidneys of spontaneously hypertensive rats","volume":"289","author":"Kim","year":"2005","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1161\/HYPERTENSIONAHA.113.01295","article-title":"Increased renal epithelial na channel expression and activity correlate with elevation of blood pressure in spontaneously hypertensive rats","volume":"62","author":"Haloui","year":"2013","journal-title":"Hypertension"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"812160","DOI":"10.1093\/ecam\/neq063","article-title":"Pulse width modulation electro-acupuncture on cardiovascular remodeling and plasma nitric oxide in spontaneously hypertensive rats","volume":"2011","author":"Xiong","year":"2011","journal-title":"Evid. Based Complement Altern. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1161\/01.RES.37.1.66","article-title":"Control of aldosterone secretion in the spontaneously hypertensive rat","volume":"37","author":"Freeman","year":"1975","journal-title":"Circ. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1161\/HYPERTENSIONAHA.116.08966","article-title":"Renal Dysfunction Induced by Kidney-Specific Gene Deletion of Hsd11b2 as a Primary Cause of Salt-Dependent Hypertension","volume":"70","author":"Ueda","year":"2017","journal-title":"Hypertension"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e13448","DOI":"10.1111\/apha.13448","article-title":"Electrolyte and transporter responses to angiotensin II induced hypertension in female and male rats and mice","volume":"229","author":"Veiras","year":"2020","journal-title":"Acta Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1074\/jbc.M111.298919","article-title":"Angiotensin II increases activity of the epithelial Na+ channel (ENaC) in distal nephron additively to aldosterone","volume":"287","author":"Mamenko","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1161\/CIRCULATIONAHA.115.019341","article-title":"Conditional Deletion of Hsd11b2 in the Brain Causes Salt Appetite and Hypertension","volume":"133","author":"Evans","year":"2016","journal-title":"Circulation"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1161\/HYPERTENSIONAHA.110.163782","article-title":"Hsd11b2 haploinsufficiency in mice causes salt sensitivity of blood pressure","volume":"57","author":"Bailey","year":"2011","journal-title":"Hypertension"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/0024-3205(89)90490-6","article-title":"Adrenocorticotropin and corticosterone levels in pre-weanling spontaneously hypertensive rats","volume":"44","author":"Ardekani","year":"1989","journal-title":"Life Sci."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Hayakawa, Y., Aoyama, T., Yokoyama, C., Okamoto, C., Komaki, H., Minatoguchi, S., Iwasa, M., Yamada, Y., Kawamura, I., and Kawasaki, M. (2015). High salt intake damages the heart through activation of cardiac (pro) renin receptors even at an early stage of hypertension. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0120453"},{"key":"ref_45","first-page":"77","article-title":"Effect of moderately high dietary salt and lipoic acid on blood pressure in Wistar-Kyoto rats","volume":"12","author":"Vasdev","year":"2007","journal-title":"Exp. Clin. Cardiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1161\/01.HYP.24.1.1","article-title":"Diurnal blood pressure variation and dietary salt in spontaneously hypertensive rats","volume":"24","author":"Calhoun","year":"1994","journal-title":"Hypertension"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6953\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T13:10:38Z","timestamp":1785762638000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6953"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,2]]},"references-count":46,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27156953"],"URL":"https:\/\/doi.org\/10.3390\/ijms27156953","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,2]]}}}