title: Transglutaminase is a Critical Link Between Inflammation and Hypertension.
abstract: The pathogenesis of essential hypertension is multifactorial with different underlying mechanisms contributing to disease. We have recently shown that TNF superfamily member 14 LIGHT (an acronym for homologous to lymphotoxins, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes, also known as TNFSF14) induces hypertension when injected into mice. Research reported here was undertaken to examine the role of transglutaminase (TGase) in LIGHT-induced hypertension.
  
  
  
  Initial experiments showed that plasma and kidney TGase activity was induced by LIGHT infusion (13.91±2.92 versus 6.75±1.92 mU/mL and 19.86±3.55 versus 12.00±0.97 mU/10 μg) and was accompanied with hypertension (169±7.16 versus 117.17±11.57 mm Hg at day 14) and renal impairment (proteinuria, 61.33±23.21 versus 20.38±9.01 μg/mg; osmolality, 879.57±93.02 versus 1407.2±308.04 mmol/kg). The increase in renal TGase activity corresponded to an increase in RNA for the tissue TGase isoform, termed TG2. Pharmacologically, we showed that LIGHT-induced hypertension and renal impairment did not occur in the presence of cystamine, a well-known competitive inhibitor of TGase activity. Genetically, we showed that LIGHT-mediated induction of TGase, along with hypertension and renal impairment, was dependent on interleukin-6 and endothelial hypoxia inducible factor-1α. We also demonstrated that interleukin-6, endothelial hypoxia inducible factor-1α, and TGase are required for LIGHT-induced production of angiotensin receptor agonistic autoantibodies.
  
  
  
  Thus, LIGHT-induced hypertension, renal impairment, and production of angiotensin receptor agonistic autoantibodies require TGase, most likely the TG2 isoform. Our findings establish TGase as a critical link between inflammation, hypertension, and autoimmunity.
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, TX Department of Nephrology, The First Xiangya Hospital of Central South University, Changsha, Hunan, PRC Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Renna
authors.initials: R
authors.lastname: Luo
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, TX.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Chemical Engineering, University of California, Santa Barbara, CA.
authors.forename: Serra E
authors.initials: SE
authors.lastname: Elliott
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, TX Department of Nephrology, The First Xiangya Hospital of Central South University, Changsha, Hunan, PRC.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, TX.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Parchim
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, TX Department of Obstetrics and Gynecology, University of Tokyo, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Iriyama
authors.affiliation: Department of Chemical Engineering, University of California, Santa Barbara, CA.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Daugherty
authors.affiliation: Department of Nephrology, The First Xiangya Hospital of Central South University, Changsha, Hunan, PRC.
authors.forename: Lijian
authors.initials: L
authors.lastname: Tao
authors.affiliation: Department of Anesthesiology, University of Colorado-Medical School, Denver, CO.
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, The University of Texas Health Science Center at Houston, TX.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Blackwell
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, The University of Texas Health Science Center at Houston, TX.
authors.forename: Baha M
authors.initials: BM
authors.lastname: Sibai
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, TX The University of Texas Graduate School of Biomedical Sciences at Houston, TX yang.xia@uth.tmc.edu rodney.e.kellems@uth.tmc.edu.
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Kellems
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, TX The University of Texas Graduate School of Biomedical Sciences at Houston, TX yang.xia@uth.tmc.edu rodney.e.kellems@uth.tmc.edu.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001794:Blood Pressure / Q000187:drug effects* / Q000276:immunology; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006973:Hypertension / Q000276:immunology* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D007668:Kidney / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011507:Proteinuria / Q000276:immunology / Q000378:metabolism; D011945:Receptors, Angiotensin / Q000276:immunology; D051437:Renal Insufficiency / Q000276:immunology / Q000378:metabolism; D011503:Transglutaminases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000494:pharmacology*
chemical_list: D001323:Autoantibodies; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015850:Interleukin-6; D011945:Receptors, Angiotensin; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; C577686:interleukin-6, mouse; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: AT1‐AA; angiotensin receptor; hypertension; inflammation; transglutaminase