RGD Reference Report - Evidence of the Importance of Nox4 in Production of Hypertension in Dahl Salt-Sensitive Rats. - Rat Genome Database

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Evidence of the Importance of Nox4 in Production of Hypertension in Dahl Salt-Sensitive Rats.

Authors: Cowley AW, JR  Yang, C  Zheleznova, NN  Staruschenko, A  Kurth, T  Rein, L  Kumar, V  Sadovnikov, K  Dayton, A  Hoffman, M  Ryan, RP  Skelton, MM  Salehpour, F  Ranji, M  Geurts, A 
Citation: Cowley AW Jr, etal., Hypertension. 2016 Feb;67(2):440-50. doi: 10.1161/HYPERTENSIONAHA.115.06280. Epub 2015 Dec 7.
RGD ID: 11085830
Pubmed: PMID:26644237   (View Abstract at PubMed)
PMCID: PMC4713301   (View Article at PubMed Central)
DOI: DOI:10.1161/HYPERTENSIONAHA.115.06280   (Journal Full-text)

This study reports the consequences of knocking out NADPH (nicotinamide adenine dinucleotide phosphate) oxidase 4 (Nox4) on the development of hypertension and kidney injury in the Dahl salt-sensitive (SS) rat. Zinc finger nuclease injection of single-cell SS embryos was used to create an 8 base-pair frame-shift deletion of Nox4, resulting in a loss of the approximately 68 kDa band in Western blot analysis of renal cortical tissue of the knock out of Nox4 in the SS rat (SS(Nox4-/-)) rats. SS(Nox4-/-) rats exhibited a significant reduction of salt-induced hypertension compared with SS rats after 21 days of 4.0% NaCl diet (134+/-5 versus 151+/-3 mm Hg in SS) and a significant reduction of albuminuria, tubular casts, and glomerular injury. Optical fluorescence 3-dimensional cryoimaging revealed significantly higher redox ratios (NADH/FAD [reduced nicotinamide adenine dinucleotide/flavin adenine dinucleotide]) in the kidneys of SS(Nox4-/-) rats even when fed the 0.4% NaCl diet, indicating greater levels of mitochondrial electron transport chain metabolic activity and reduced oxidative stress compared with SS rats. Before the development of hypertension, RNA expression levels of Nox subunits Nox2, p67(phox), and p22(phox) were found to be significantly lower (P<0.05) in SS(Nox4-/-) compared with SS rats in the renal cortex. Thus, the mutation of Nox4 seems to modify transcription of several genes in ways that contribute to the protective effects observed in the SS(Nox4-/-) rats. We conclude that the reduced renal injury and attenuated blood pressure response to high salt in the SS(Nox4-/-) rat could be the result of multiple pathways, including gene transcription, mitochondrial energetics, oxidative stress, and protein matrix production impacted by the knock out of Nox4.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
NOX4Humanhypertension  ISONox4 (Rattus norvegicus) RGD 
Nox4Rathypertension  IMP  RGD 
Nox4Mousehypertension  ISONox4 (Rattus norvegicus) RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Nox4Ratdecreased mean systemic arterial blood pressure inducedIMPcontrolled sodium content diet RGD 
Nox4Ratdecreased mean systemic arterial blood pressure  IMP compared to SS/JrHsdMcwiRGD 
Nox4em2McwiRatdecreased mean systemic arterial blood pressure inducedIMPcontrolled sodium content diet RGD 
Nox4em2McwiRatdecreased mean systemic arterial blood pressure  IMP compared to SS/JrHsdMcwiRGD 
SS-Nox4em2Mcwi-/-Ratdecreased mean systemic arterial blood pressure inducedIMPcontrolled sodium content dietcompared to SS/JrHsdMcwiRGD 
Nox4Ratdecreased susceptibility to hypertension inducedIMPcontrolled sodium content diet RGD 
Nox4Ratdecreased susceptibility to hypertension  IMP compared to SS/JrHsdMcwiRGD 
Nox4em2McwiRatdecreased susceptibility to hypertension inducedIMPcontrolled sodium content diet RGD 
Nox4em2McwiRatdecreased susceptibility to hypertension  IMP compared to SS/JrHsdMcwiRGD 
SS-Nox4em2Mcwi-/-Ratdecreased susceptibility to hypertension inducedIMPcontrolled sodium content dietcompared to SS/JrHsdMcwiRGD 
Nox4Ratdecreased urine albumin level inducedIMPcontrolled sodium content diet RGD 
Nox4Ratdecreased urine albumin level  IMP compared to SS/JrHsdMcwiRGD 
Nox4em2McwiRatdecreased urine albumin level inducedIMPcontrolled sodium content diet RGD 
Nox4em2McwiRatdecreased urine albumin level  IMP compared to SS/JrHsdMcwiRGD 
SS-Nox4em2Mcwi-/-Ratdecreased urine albumin level inducedIMPcontrolled sodium content dietcompared to SS/JrHsdMcwiRGD 
Nox4Ratoxidative stress severityIMP  RGD 
Nox4em2McwiRatoxidative stress severityIMP  RGD 
SS-Nox4em2Mcwi-/-Ratoxidative stress severityIMP compared to SS/JrHsdMcwiRGD 
Nox4Ratsalt-sensitive hypertension severityIMP  RGD 

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Objects Annotated

Genes (Rattus norvegicus)
Nox4  (NADPH oxidase 4)
Nox4em2Mcwi  (NADPH oxidase 4; zinc finger nuclease induced mutant 2, Medical College of Wisconsin)

Genes (Mus musculus)
Nox4  (NADPH oxidase 4)

Genes (Homo sapiens)
NOX4  (NADPH oxidase 4)

Strains
SS-Nox4em2Mcwi-/-  (SS-Nox4em2Mcwi-/Nox4em2Mcwi-)

Objects referenced in this article
Strain SS-Nox4em1Mcwi null Rattus norvegicus
Strain SS-Nox4em2Mcwi null Rattus norvegicus

Additional Information