title: Sex-specific T-cell regulation of angiotensin II-dependent hypertension.
abstract: Studies suggest T cells modulate arterial pressure. Because robust sex differences exist in the immune system and in hypertension, we investigated sex differences in T-cell modulation of angiotensin II-induced increases in mean arterial pressure in male (M) and female (F) wild-type and recombination-activating-gene-1-deficient (Rag1(-/-)) mice. Sex differences in peak mean arterial pressure in wild-type were lost in Rag1(-/-) mice (mm Hg: wild-type-F, 136±4.9 versus wild-type-M, 153±1.7; P<0.02; Rag1(-/-)-F, 135±2.1 versus Rag1(-/-)-M, 141±3.8). Peak mean arterial pressure was 13 mm Hg higher after adoptive transfer of male (CD3(M)→Rag1(-/-)-M) versus female (CD3(F)→Rag1(-/-)-M) T cells. CD3(M)→Rag1(-/-)-M mice exhibited higher splenic frequencies of proinflammatory interleukin-17A (2.4-fold) and tumor necrosis factor-α (2.2-fold)-producing T cells and lower plasma levels (13-fold) and renal mRNA expression (2.4-fold) of interleukin-10, whereas CD3(F)→Rag1(-/-)-M mice displayed a higher activation state in general and T-helper-1-biased renal inflammation. Greater T-cell infiltration into perivascular adipose tissue and kidney associated with increased pressor responses to angiotensin II if the T cell donor was male but not female and these sex differences in T-cell subset expansion and tissue infiltration were maintained for 7 to 8 weeks within the male host. Thus, the adaptive immune response and role of pro- and anti-inflammatory cytokine signaling in hypertension are distinct between the sexes and need to be understood to improve therapeutics for hypertension-associated disease in both men and women.
authors.affiliation: From the Department of Medicine and Center for the Study of Sex Differences in Health, Aging, and Disease (H.J., W.Z., X.L., J.L., X.W., J.G.U., K.S.) and Department of Pharmacology and Physiology and Center for Development of Radioligands (R.C.S.), Georgetown University, Washington, DC; Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Science, Jilin University, Changchun, Jilin, People's Republic of China (X.L.); Biorepository and Biochemistry Laboratory, MedStar Health Research Institute, Hyattsville, MD (J.G.U.); Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, DC (H.J., W.Z., X.L., J.L., X.W., J.G.U., K.S.); Department of Physiology and the Evelyn F. McKnight Brain Institute, University of Arizona at Tucson (M.H.); Department of Pharmaceutical Sciences, College of Pharmacy, Nova South Eastern University, Fort Lauderdale, FL (R.C.S.); Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada (M.A.Z., S.E.D.); Department of Immunology, University of Toronto, Toronto, Ontario, Canada (M.A.Z., S.E.D.); and Women's College Research Institute, Toronto, Ontario, Canada (S.E.D.). jih@georgetown.edu.
authors.forename: Hong
authors.initials: H
authors.lastname: Ji
authors.affiliation: From the Department of Medicine and Center for the Study of Sex Differences in Health, Aging, and Disease (H.J., W.Z., X.L., J.L., X.W., J.G.U., K.S.) and Department of Pharmacology and Physiology and Center for Development of Radioligands (R.C.S.), Georgetown University, Washington, DC; Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Science, Jilin University, Changchun, Jilin, People's Republic of China (X.L.); Biorepository and Biochemistry Laboratory, MedStar Health Research Institute, Hyattsville, MD (J.G.U.); Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, DC (H.J., W.Z., X.L., J.L., X.W., J.G.U., K.S.); Department of Physiology and the Evelyn F. McKnight Brain Institute, University of Arizona at Tucson (M.H.); Department of Pharmaceutical Sciences, College of Pharmacy, Nova South Eastern University, Fort Lauderdale, FL (R.C.S.); Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada (M.A.Z., S.E.D.); Department of Immunology, University of Toronto, Toronto, Ontario, Canada (M.A.Z., S.E.D.); and Women's College Research Institute, Toronto, Ontario, Canada (S.E.D.).
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: From the Department of Medicine and Center for the Study of Sex Differences in Health, Aging, and Disease (H.J., W.Z., X.L., J.L., X.W., J.G.U., K.S.) and Department of Pharmacology and Physiology and Center for Development of Radioligands (R.C.S.), Georgetown University, Washington, DC; Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Science, Jilin University, Changchun, Jilin, People's Republic of China (X.L.); Biorepository and Biochemistry Laboratory, MedStar Health Research Institute, Hyattsville, MD (J.G.U.); Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, DC (H.J., W.Z., X.L., J.L., X.W., J.G.U., K.S.); Department of Physiology and the Evelyn F. McKnight Brain Institute, University of Arizona at Tucson (M.H.); Department of Pharmaceutical Sciences, College of Pharmacy, Nova South Eastern University, Fort Lauderdale, FL (R.C.S.); Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada (M.A.Z., S.E.D.); Department of Immunology, University of Toronto, Toronto, Ontario, Canada (M.A.Z., S.E.D.); and Women's College Research Institute, Toronto, Ontario, Canada (S.E.D.).
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Li
authors.affiliation: From the Department of Medicine and Center for the Study of Sex Differences in Health, Aging, and Disease (H.J., W.Z., X.L., J.L., X.W., J.G.U., K.S.) and Department of Pharmacology and Physiology and Center for Development of Radioligands (R.C.S.), Georgetown University, Washington, DC; Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Science, Jilin University, Changchun, Jilin, People's Republic of China (X.L.); Biorepository and Biochemistry Laboratory, MedStar Health Research Institute, Hyattsville, MD (J.G.U.); Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, DC (H.J., W.Z., X.L., J.L., X.W., J.G.U., K.S.); Department of Physiology and the Evelyn F. McKnight Brain Institute, University of Arizona at Tucson (M.H.); Department of Pharmaceutical Sciences, College of Pharmacy, Nova South Eastern University, Fort Lauderdale, FL (R.C.S.); Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada (M.A.Z., S.E.D.); Department of Immunology, University of Toronto, Toronto, Ontario, Canada (M.A.Z., S.E.D.); and Women's College Research Institute, Toronto, Ontario, Canada (S.E.D.).
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: From the Department of Medicine and Center for the Study of Sex Differences in Health, Aging, and Disease (H.J., W.Z., X.L., J.L., X.W., J.G.U., K.S.) and Department of Pharmacology and Physiology and Center for Development of Radioligands (R.C.S.), Georgetown University, Washington, DC; Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Science, Jilin University, Changchun, Jilin, People's Republic of China (X.L.); Biorepository and Biochemistry Laboratory, MedStar Health Research Institute, Hyattsville, MD (J.G.U.); Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, DC (H.J., W.Z., X.L., J.L., X.W., J.G.U., K.S.); Department of Physiology and the Evelyn F. McKnight Brain Institute, University of Arizona at Tucson (M.H.); Department of Pharmaceutical Sciences, College of Pharmacy, Nova South Eastern University, Fort Lauderdale, FL (R.C.S.); Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada (M.A.Z., S.E.D.); Department of Immunology, University of Toronto, Toronto, Ontario, Canada (M.A.Z., S.E.D.); and Women's College Research Institute, Toronto, Ontario, Canada (S.E.D.).
authors.forename: Xie
authors.initials: X
authors.lastname: Wu
authors.affiliation: From the Department of Medicine and Center for the Study of Sex Differences in Health, Aging, and Disease (H.J., W.Z., X.L., J.L., X.W., J.G.U., K.S.) and Department of Pharmacology and Physiology and Center for Development of Radioligands (R.C.S.), Georgetown University, Washington, DC; Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Science, Jilin University, Changchun, Jilin, People's Republic of China (X.L.); Biorepository and Biochemistry Laboratory, MedStar Health Research Institute, Hyattsville, MD (J.G.U.); Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, DC (H.J., W.Z., X.L., J.L., X.W., J.G.U., K.S.); Department of Physiology and the Evelyn F. McKnight Brain Institute, University of Arizona at Tucson (M.H.); Department of Pharmaceutical Sciences, College of Pharmacy, Nova South Eastern University, Fort Lauderdale, FL (R.C.S.); Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada (M.A.Z., S.E.D.); Department of Immunology, University of Toronto, Toronto, Ontario, Canada (M.A.Z., S.E.D.); and Women's College Research Institute, Toronto, Ontario, Canada (S.E.D.).
authors.forename: Monan Angela
authors.initials: MA
authors.lastname: Zhang
authors.affiliation: From the Department of Medicine and Center for the Study of Sex Differences in Health, Aging, and Disease (H.J., W.Z., X.L., J.L., X.W., J.G.U., K.S.) and Department of Pharmacology and Physiology and Center for Development of Radioligands (R.C.S.), Georgetown University, Washington, DC; Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Science, Jilin University, Changchun, Jilin, People's Republic of China (X.L.); Biorepository and Biochemistry Laboratory, MedStar Health Research Institute, Hyattsville, MD (J.G.U.); Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, DC (H.J., W.Z., X.L., J.L., X.W., J.G.U., K.S.); Department of Physiology and the Evelyn F. McKnight Brain Institute, University of Arizona at Tucson (M.H.); Department of Pharmaceutical Sciences, College of Pharmacy, Nova South Eastern University, Fort Lauderdale, FL (R.C.S.); Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada (M.A.Z., S.E.D.); Department of Immunology, University of Toronto, Toronto, Ontario, Canada (M.A.Z., S.E.D.); and Women's College Research Institute, Toronto, Ontario, Canada (S.E.D.).
authors.forename: Jason G
authors.initials: JG
authors.lastname: Umans
authors.affiliation: From the Department of Medicine and Center for the Study of Sex Differences in Health, Aging, and Disease (H.J., W.Z., X.L., J.L., X.W., J.G.U., K.S.) and Department of Pharmacology and Physiology and Center for Development of Radioligands (R.C.S.), Georgetown University, Washington, DC; Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Science, Jilin University, Changchun, Jilin, People's Republic of China (X.L.); Biorepository and Biochemistry Laboratory, MedStar Health Research Institute, Hyattsville, MD (J.G.U.); Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, DC (H.J., W.Z., X.L., J.L., X.W., J.G.U., K.S.); Department of Physiology and the Evelyn F. McKnight Brain Institute, University of Arizona at Tucson (M.H.); Department of Pharmaceutical Sciences, College of Pharmacy, Nova South Eastern University, Fort Lauderdale, FL (R.C.S.); Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada (M.A.Z., S.E.D.); Department of Immunology, University of Toronto, Toronto, Ontario, Canada (M.A.Z., S.E.D.); and Women's College Research Institute, Toronto, Ontario, Canada (S.E.D.).
authors.forename: Meredith
authors.initials: M
authors.lastname: Hay
authors.affiliation: From the Department of Medicine and Center for the Study of Sex Differences in Health, Aging, and Disease (H.J., W.Z., X.L., J.L., X.W., J.G.U., K.S.) and Department of Pharmacology and Physiology and Center for Development of Radioligands (R.C.S.), Georgetown University, Washington, DC; Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Science, Jilin University, Changchun, Jilin, People's Republic of China (X.L.); Biorepository and Biochemistry Laboratory, MedStar Health Research Institute, Hyattsville, MD (J.G.U.); Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, DC (H.J., W.Z., X.L., J.L., X.W., J.G.U., K.S.); Department of Physiology and the Evelyn F. McKnight Brain Institute, University of Arizona at Tucson (M.H.); Department of Pharmaceutical Sciences, College of Pharmacy, Nova South Eastern University, Fort Lauderdale, FL (R.C.S.); Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada (M.A.Z., S.E.D.); Department of Immunology, University of Toronto, Toronto, Ontario, Canada (M.A.Z., S.E.D.); and Women's College Research Institute, Toronto, Ontario, Canada (S.E.D.).
authors.forename: Robert C
authors.initials: RC
authors.lastname: Speth
authors.affiliation: From the Department of Medicine and Center for the Study of Sex Differences in Health, Aging, and Disease (H.J., W.Z., X.L., J.L., X.W., J.G.U., K.S.) and Department of Pharmacology and Physiology and Center for Development of Radioligands (R.C.S.), Georgetown University, Washington, DC; Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Science, Jilin University, Changchun, Jilin, People's Republic of China (X.L.); Biorepository and Biochemistry Laboratory, MedStar Health Research Institute, Hyattsville, MD (J.G.U.); Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, DC (H.J., W.Z., X.L., J.L., X.W., J.G.U., K.S.); Department of Physiology and the Evelyn F. McKnight Brain Institute, University of Arizona at Tucson (M.H.); Department of Pharmaceutical Sciences, College of Pharmacy, Nova South Eastern University, Fort Lauderdale, FL (R.C.S.); Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada (M.A.Z., S.E.D.); Department of Immunology, University of Toronto, Toronto, Ontario, Canada (M.A.Z., S.E.D.); and Women's College Research Institute, Toronto, Ontario, Canada (S.E.D.).
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Dunn
authors.affiliation: From the Department of Medicine and Center for the Study of Sex Differences in Health, Aging, and Disease (H.J., W.Z., X.L., J.L., X.W., J.G.U., K.S.) and Department of Pharmacology and Physiology and Center for Development of Radioligands (R.C.S.), Georgetown University, Washington, DC; Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Science, Jilin University, Changchun, Jilin, People's Republic of China (X.L.); Biorepository and Biochemistry Laboratory, MedStar Health Research Institute, Hyattsville, MD (J.G.U.); Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, DC (H.J., W.Z., X.L., J.L., X.W., J.G.U., K.S.); Department of Physiology and the Evelyn F. McKnight Brain Institute, University of Arizona at Tucson (M.H.); Department of Pharmaceutical Sciences, College of Pharmacy, Nova South Eastern University, Fort Lauderdale, FL (R.C.S.); Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada (M.A.Z., S.E.D.); Department of Immunology, University of Toronto, Toronto, Ontario, Canada (M.A.Z., S.E.D.); and Women's College Research Institute, Toronto, Ontario, Canada (S.E.D.).
authors.forename: Kathryn
authors.initials: K
authors.lastname: Sandberg
mesh_terms: D056704:Adaptive Immunity / Q000502:physiology; D000804:Angiotensin II / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D006973:Hypertension / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D016753:Interleukin-10 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012737:Sex Factors; D013601:T-Lymphocytes / Q000473:pathology* / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D020381:Interleukin-17; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; C064658:RAG-1 protein; D016753:Interleukin-10
keywords: T-lymphocytes; angiotensins; hypertension; interleukin 10 interleukin 17; sex characteristics; tumor necrosis factor-alpha