title: B-Type Natriuretic Peptide Deletion Leads to Progressive Hypertension, Associated Organ Damage, and Reduced Survival: Novel Model for Human Hypertension.
abstract: Altered myocardial structure and function, secondary to chronically elevated blood pressure, are leading causes of heart failure and death. B-type natriuretic peptide (BNP), a guanylyl cyclase A agonist, is a cardiac hormone integral to cardiovascular regulation. Studies have demonstrated a causal relationship between reduced production or impaired BNP release and the development of human hypertension. However, the consequences of BNP insufficiency on blood pressure and hypertension-associated complications remain poorly understood. Therefore, the goal of this study was to create and characterize a novel model of BNP deficiency to investigate the effects of BNP absence on cardiac and renal structure, function, and survival. Genetic BNP deletion was generated in Dahl salt-sensitive rats. Compared with age-matched controls, BNP knockout rats demonstrated adult-onset hypertension. Increased left ventricular mass with hypertrophy and substantially augmented hypertrophy signaling pathway genes, developed in young adult knockout rats, which preceded hypertension. Prolonged hypertension led to increased cardiac stiffness, cardiac fibrosis, and thrombi formation. Significant elongation of the QT interval was detected at 9 months in knockout rats. Progressive nephropathy was also noted with proteinuria, fibrosis, and glomerular alterations in BNP knockout rats. End-organ damage contributed to a significant decline in overall survival. Systemic BNP overexpression reversed the phenotype of genetic BNP deletion. Our results demonstrate the critical role of BNP defect in the development of systemic hypertension and associated end-organ damage in adulthood.
authors.affiliation: From the Department of Molecular Medicine (S.J.H., C.A.S., R.N., J.M.T., K.-W.P., Y.I.) and Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Departments of Medicine and Physiology (J.C.B., A.C.), Mayo Clinic, College of Medicine, Rochester, MN; Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee (A.G., H.J.J.); and Institute for Experimental Medical Research, Oslo University Hospital, University of Oslo, Oslo, Norway (A.C.).
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Holditch
authors.affiliation: From the Department of Molecular Medicine (S.J.H., C.A.S., R.N., J.M.T., K.-W.P., Y.I.) and Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Departments of Medicine and Physiology (J.C.B., A.C.), Mayo Clinic, College of Medicine, Rochester, MN; Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee (A.G., H.J.J.); and Institute for Experimental Medical Research, Oslo University Hospital, University of Oslo, Oslo, Norway (A.C.).
authors.forename: Claire A
authors.initials: CA
authors.lastname: Schreiber
authors.affiliation: From the Department of Molecular Medicine (S.J.H., C.A.S., R.N., J.M.T., K.-W.P., Y.I.) and Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Departments of Medicine and Physiology (J.C.B., A.C.), Mayo Clinic, College of Medicine, Rochester, MN; Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee (A.G., H.J.J.); and Institute for Experimental Medical Research, Oslo University Hospital, University of Oslo, Oslo, Norway (A.C.).
authors.forename: Ryan
authors.initials: R
authors.lastname: Nini
authors.affiliation: From the Department of Molecular Medicine (S.J.H., C.A.S., R.N., J.M.T., K.-W.P., Y.I.) and Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Departments of Medicine and Physiology (J.C.B., A.C.), Mayo Clinic, College of Medicine, Rochester, MN; Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee (A.G., H.J.J.); and Institute for Experimental Medical Research, Oslo University Hospital, University of Oslo, Oslo, Norway (A.C.).
authors.forename: Jason M
authors.initials: JM
authors.lastname: Tonne
authors.affiliation: From the Department of Molecular Medicine (S.J.H., C.A.S., R.N., J.M.T., K.-W.P., Y.I.) and Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Departments of Medicine and Physiology (J.C.B., A.C.), Mayo Clinic, College of Medicine, Rochester, MN; Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee (A.G., H.J.J.); and Institute for Experimental Medical Research, Oslo University Hospital, University of Oslo, Oslo, Norway (A.C.).
authors.forename: Kah-Whye
authors.initials: KW
authors.lastname: Peng
authors.affiliation: From the Department of Molecular Medicine (S.J.H., C.A.S., R.N., J.M.T., K.-W.P., Y.I.) and Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Departments of Medicine and Physiology (J.C.B., A.C.), Mayo Clinic, College of Medicine, Rochester, MN; Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee (A.G., H.J.J.); and Institute for Experimental Medical Research, Oslo University Hospital, University of Oslo, Oslo, Norway (A.C.).
authors.forename: Aron
authors.initials: A
authors.lastname: Geurts
authors.affiliation: From the Department of Molecular Medicine (S.J.H., C.A.S., R.N., J.M.T., K.-W.P., Y.I.) and Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Departments of Medicine and Physiology (J.C.B., A.C.), Mayo Clinic, College of Medicine, Rochester, MN; Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee (A.G., H.J.J.); and Institute for Experimental Medical Research, Oslo University Hospital, University of Oslo, Oslo, Norway (A.C.).
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Jacob
authors.affiliation: From the Department of Molecular Medicine (S.J.H., C.A.S., R.N., J.M.T., K.-W.P., Y.I.) and Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Departments of Medicine and Physiology (J.C.B., A.C.), Mayo Clinic, College of Medicine, Rochester, MN; Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee (A.G., H.J.J.); and Institute for Experimental Medical Research, Oslo University Hospital, University of Oslo, Oslo, Norway (A.C.).
authors.forename: John C
authors.initials: JC
authors.lastname: Burnett
authors.affiliation: From the Department of Molecular Medicine (S.J.H., C.A.S., R.N., J.M.T., K.-W.P., Y.I.) and Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Departments of Medicine and Physiology (J.C.B., A.C.), Mayo Clinic, College of Medicine, Rochester, MN; Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee (A.G., H.J.J.); and Institute for Experimental Medical Research, Oslo University Hospital, University of Oslo, Oslo, Norway (A.C.).
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cataliotti
authors.affiliation: From the Department of Molecular Medicine (S.J.H., C.A.S., R.N., J.M.T., K.-W.P., Y.I.) and Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Departments of Medicine and Physiology (J.C.B., A.C.), Mayo Clinic, College of Medicine, Rochester, MN; Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee (A.G., H.J.J.); and Institute for Experimental Medical Research, Oslo University Hospital, University of Oslo, Oslo, Norway (A.C.). Ikeda.yasuhiro@mayo.edu.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ikeda
mesh_terms: D017668:Age of Onset; D000818:Animals; D003187:Compliance; D016757:Death, Sudden, Cardiac / Q000209:etiology; D004195:Disease Models, Animal; D005355:Fibrosis; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D006801:Humans; D006973:Hypertension / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000473:pathology; D007678:Kidney Glomerulus / Q000473:pathology; D008133:Long QT Syndrome / Q000209:etiology; D009200:Myocardial Contraction / Q000235:genetics; D009206:Myocardium / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D051381:Rats; D020303:Rats, Inbred Dahl; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000209:etiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D011993:Recombinant Fusion Proteins; C495963:natriuretic peptide precursor type B, rat; D020097:Natriuretic Peptide, Brain
keywords: b-type natriuretic factor; fibrosis; hypertrophy