RGD Reference Report - B-Type Natriuretic Peptide Deletion Leads to Progressive Hypertension, Associated Organ Damage, and Reduced Survival: Novel Model for Human Hypertension. - Rat Genome Database

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B-Type Natriuretic Peptide Deletion Leads to Progressive Hypertension, Associated Organ Damage, and Reduced Survival: Novel Model for Human Hypertension.

Authors: Holditch, Sara J  Schreiber, Claire A  Nini, Ryan  Tonne, Jason M  Peng, Kah-Whye  Geurts, Aron  Jacob, Howard J  Burnett, John C  Cataliotti, Alessandro  Ikeda, Yasuhiro 
Citation: Holditch SJ, etal., Hypertension. 2015 Jul;66(1):199-210. doi: 10.1161/HYPERTENSIONAHA.115.05610. Epub 2015 May 11.
RGD ID: 12910116
Pubmed: PMID:26063669   (View Abstract at PubMed)
PMCID: PMC4467451   (View Article at PubMed Central)
DOI: DOI:10.1161/HYPERTENSIONAHA.115.05610   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Hypertensive Nephropathy  ISONppb (Rattus norvegicus)12910116; 12910116 RGD 
Hypertensive Nephropathy  IMP 12910116; 12910116 RGD 
Hypertensive Nephropathy MODEL: age-relatedIMP 12910116 RGD 
proteinuria  IMP 12910116 RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

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Objects Annotated

Genes (Rattus norvegicus)
Nppb  (natriuretic peptide B)
Nppbem2Mcwi  (natriuretic peptide B; zinc finger nuclease induced mutant 2, Medical College of Wisconsin)

Genes (Mus musculus)
Nppb  (natriuretic peptide type B)

Genes (Homo sapiens)
NPPB  (natriuretic peptide B)

SS-Nppbem2Mcwi-/-  (SS-Nppbem2Mcwi-/Nppbem2Mcwi-)

Additional Information