title: Angiotensinogen Exerts Effects Independent of Angiotensin II.
abstract: OBJECTIVE
  This study determined whether angiotensinogen (AGT) has angiotensin II-independent effects using multiple genetic and pharmacological manipulations.
  
  
  RESULTS
  All study mice were in low-density lipoprotein receptor -/- background and fed a saturated fat-enriched diet. In mice with floxed alleles and a neomycin cassette in intron 2 of the AGT gene (hypoAGT mice), plasma AGT concentrations were >90% lower compared with their wild-type littermates. HypoAGT mice had lower systolic blood pressure, less atherosclerosis, and diminished body weight gain and liver steatosis. Low plasma AGT concentrations and all phenotypes were recapitulated in mice with hepatocyte-specific deficiency of AGT or pharmacological inhibition of AGT by antisense oligonucleotide administration. In contrast, inhibition of AGT cleavage by a renin inhibitor, aliskiren, failed to alter body weight gain and liver steatosis in low-density lipoprotein receptor -/- mice. In mice with established adiposity, administration of AGT antisense oligonucleotide versus aliskiren led to equivalent reductions of systolic blood pressure and atherosclerosis. AGT antisense oligonucleotide administration ceased body weight gain and further reduced body weight, whereas aliskiren did not affect body weight gain during continuous saturated fat-enriched diet feeding. Structural comparisons of AGT proteins in zebrafish, mouse, rat, and human revealed 4 highly conserved sequences within the des(angiotensin I)AGT domain. des(angiotensin I)AGT, through adeno-associated viral infection in hepatocyte-specific AGT-deficient mice, increased body weight gain and liver steatosis, but did not affect atherosclerosis.
  
  
  CONCLUSIONS
  AGT contributes to body weight gain and liver steatosis through functions of the des(angiotensin I)AGT domain, which are independent of angiotensin II production.
authors.affiliation: From the Saha Cardiovascular Research Center (H.L., C.W., D.A.H., A.B., J.J.M., X.C., M.Z., A.D.); Departments of Physiology (H.L., A.D.), Pharmacology and Nutritional Sciences (C.W., L.A.C., A.D.), and Molecular and Cellular Biochemistry (C.W.V.K.), University of Kentucky, Lexington; Isis Pharmaceuticals, Inc, Carlsbad, CA (M.J.G., A.E.M., R.M.C.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (D.L.F.).
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.affiliation: From the Saha Cardiovascular Research Center (H.L., C.W., D.A.H., A.B., J.J.M., X.C., M.Z., A.D.); Departments of Physiology (H.L., A.D.), Pharmacology and Nutritional Sciences (C.W., L.A.C., A.D.), and Molecular and Cellular Biochemistry (C.W.V.K.), University of Kentucky, Lexington; Isis Pharmaceuticals, Inc, Carlsbad, CA (M.J.G., A.E.M., R.M.C.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (D.L.F.).
authors.forename: Congqing
authors.initials: C
authors.lastname: Wu
authors.affiliation: From the Saha Cardiovascular Research Center (H.L., C.W., D.A.H., A.B., J.J.M., X.C., M.Z., A.D.); Departments of Physiology (H.L., A.D.), Pharmacology and Nutritional Sciences (C.W., L.A.C., A.D.), and Molecular and Cellular Biochemistry (C.W.V.K.), University of Kentucky, Lexington; Isis Pharmaceuticals, Inc, Carlsbad, CA (M.J.G., A.E.M., R.M.C.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (D.L.F.).
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Howatt
authors.affiliation: From the Saha Cardiovascular Research Center (H.L., C.W., D.A.H., A.B., J.J.M., X.C., M.Z., A.D.); Departments of Physiology (H.L., A.D.), Pharmacology and Nutritional Sciences (C.W., L.A.C., A.D.), and Molecular and Cellular Biochemistry (C.W.V.K.), University of Kentucky, Lexington; Isis Pharmaceuticals, Inc, Carlsbad, CA (M.J.G., A.E.M., R.M.C.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (D.L.F.).
authors.forename: Anju
authors.initials: A
authors.lastname: Balakrishnan
authors.affiliation: From the Saha Cardiovascular Research Center (H.L., C.W., D.A.H., A.B., J.J.M., X.C., M.Z., A.D.); Departments of Physiology (H.L., A.D.), Pharmacology and Nutritional Sciences (C.W., L.A.C., A.D.), and Molecular and Cellular Biochemistry (C.W.V.K.), University of Kentucky, Lexington; Isis Pharmaceuticals, Inc, Carlsbad, CA (M.J.G., A.E.M., R.M.C.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (D.L.F.).
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Moorleghen
authors.affiliation: From the Saha Cardiovascular Research Center (H.L., C.W., D.A.H., A.B., J.J.M., X.C., M.Z., A.D.); Departments of Physiology (H.L., A.D.), Pharmacology and Nutritional Sciences (C.W., L.A.C., A.D.), and Molecular and Cellular Biochemistry (C.W.V.K.), University of Kentucky, Lexington; Isis Pharmaceuticals, Inc, Carlsbad, CA (M.J.G., A.E.M., R.M.C.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (D.L.F.).
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Chen
authors.affiliation: From the Saha Cardiovascular Research Center (H.L., C.W., D.A.H., A.B., J.J.M., X.C., M.Z., A.D.); Departments of Physiology (H.L., A.D.), Pharmacology and Nutritional Sciences (C.W., L.A.C., A.D.), and Molecular and Cellular Biochemistry (C.W.V.K.), University of Kentucky, Lexington; Isis Pharmaceuticals, Inc, Carlsbad, CA (M.J.G., A.E.M., R.M.C.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (D.L.F.).
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: From the Saha Cardiovascular Research Center (H.L., C.W., D.A.H., A.B., J.J.M., X.C., M.Z., A.D.); Departments of Physiology (H.L., A.D.), Pharmacology and Nutritional Sciences (C.W., L.A.C., A.D.), and Molecular and Cellular Biochemistry (C.W.V.K.), University of Kentucky, Lexington; Isis Pharmaceuticals, Inc, Carlsbad, CA (M.J.G., A.E.M., R.M.C.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (D.L.F.).
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Graham
authors.affiliation: From the Saha Cardiovascular Research Center (H.L., C.W., D.A.H., A.B., J.J.M., X.C., M.Z., A.D.); Departments of Physiology (H.L., A.D.), Pharmacology and Nutritional Sciences (C.W., L.A.C., A.D.), and Molecular and Cellular Biochemistry (C.W.V.K.), University of Kentucky, Lexington; Isis Pharmaceuticals, Inc, Carlsbad, CA (M.J.G., A.E.M., R.M.C.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (D.L.F.).
authors.forename: Adam E
authors.initials: AE
authors.lastname: Mullick
authors.affiliation: From the Saha Cardiovascular Research Center (H.L., C.W., D.A.H., A.B., J.J.M., X.C., M.Z., A.D.); Departments of Physiology (H.L., A.D.), Pharmacology and Nutritional Sciences (C.W., L.A.C., A.D.), and Molecular and Cellular Biochemistry (C.W.V.K.), University of Kentucky, Lexington; Isis Pharmaceuticals, Inc, Carlsbad, CA (M.J.G., A.E.M., R.M.C.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (D.L.F.).
authors.forename: Rosanne M
authors.initials: RM
authors.lastname: Crooke
authors.affiliation: From the Saha Cardiovascular Research Center (H.L., C.W., D.A.H., A.B., J.J.M., X.C., M.Z., A.D.); Departments of Physiology (H.L., A.D.), Pharmacology and Nutritional Sciences (C.W., L.A.C., A.D.), and Molecular and Cellular Biochemistry (C.W.V.K.), University of Kentucky, Lexington; Isis Pharmaceuticals, Inc, Carlsbad, CA (M.J.G., A.E.M., R.M.C.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (D.L.F.).
authors.forename: David L
authors.initials: DL
authors.lastname: Feldman
authors.affiliation: From the Saha Cardiovascular Research Center (H.L., C.W., D.A.H., A.B., J.J.M., X.C., M.Z., A.D.); Departments of Physiology (H.L., A.D.), Pharmacology and Nutritional Sciences (C.W., L.A.C., A.D.), and Molecular and Cellular Biochemistry (C.W.V.K.), University of Kentucky, Lexington; Isis Pharmaceuticals, Inc, Carlsbad, CA (M.J.G., A.E.M., R.M.C.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (D.L.F.).
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cassis
authors.affiliation: From the Saha Cardiovascular Research Center (H.L., C.W., D.A.H., A.B., J.J.M., X.C., M.Z., A.D.); Departments of Physiology (H.L., A.D.), Pharmacology and Nutritional Sciences (C.W., L.A.C., A.D.), and Molecular and Cellular Biochemistry (C.W.V.K.), University of Kentucky, Lexington; Isis Pharmaceuticals, Inc, Carlsbad, CA (M.J.G., A.E.M., R.M.C.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (D.L.F.).
authors.forename: Craig W
authors.initials: CW
authors.lastname: Vander Kooi
authors.affiliation: From the Saha Cardiovascular Research Center (H.L., C.W., D.A.H., A.B., J.J.M., X.C., M.Z., A.D.); Departments of Physiology (H.L., A.D.), Pharmacology and Nutritional Sciences (C.W., L.A.C., A.D.), and Molecular and Cellular Biochemistry (C.W.V.K.), University of Kentucky, Lexington; Isis Pharmaceuticals, Inc, Carlsbad, CA (M.J.G., A.E.M., R.M.C.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (D.L.F.). Alan.Daugherty@uky.edu.
authors.forename: Alan
authors.initials: A
authors.lastname: Daugherty
mesh_terms: D000577:Amides / Q000494:pharmacology; D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000378:metabolism*; D000808:Angiotensinogen / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D001794:Blood Pressure; D017124:Conserved Sequence; D000229:Dependovirus / Q000235:genetics; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D005650:Fumarates / Q000494:pharmacology; D005822:Genetic Vectors; D005838:Genotype; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012083:Renin / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014161:Transduction, Genetic; D015430:Weight Gain; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000804:Angiotensin II; D000808:Angiotensinogen; D005650:Fumarates; D016376:Oligonucleotides, Antisense; D011973:Receptors, LDL; D012083:Renin; D000092502:Renin Inhibitors; C534932:Agt protein, mouse; C446481:aliskiren
keywords: angiotensinogen; atherosclerosis; blood pressure; liver steatosis; obesity