RGD Reference Report - Genetic susceptibility and loss of Nr4a1 enhances macrophage-mediated renal injury in CKD. - Rat Genome Database

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Genetic susceptibility and loss of Nr4a1 enhances macrophage-mediated renal injury in CKD.

Authors: Westbrook, Lindsey  Johnson, Ashley C  Regner, Kevin R  Williams, Jan M  Mattson, David L  Kyle, Patrick B  Henegar, Jeffery R  Garrett, Michael R 
Citation: Westbrook L, etal., J Am Soc Nephrol. 2014 Nov;25(11):2499-510. doi: 10.1681/ASN.2013070786. Epub 2014 Apr 10.
RGD ID: 12910103
Pubmed: PMID:24722447   (View Abstract at PubMed)
PMCID: PMC4214519   (View Article at PubMed Central)
DOI: DOI:10.1681/ASN.2013070786   (Journal Full-text)

Nuclear hormone receptors of the NR4A subgroup have been implicated in cancer, atherosclerosis, and metabolic disease. However, little is known about the role of these receptors in kidney health or disease. Nr4a1-deficient rats (Nr4a1(-/-)) developed on a genetic background susceptible to kidney injury (fawn-hooded hypertensive rat [FHH]) were evaluated for BP, proteinuria, renal function, and metabolic parameters from 4 to 24 weeks-of-age. By week 24, Nr4a1(-/-) rats exhibited significantly higher proteinuria (approximately 4-fold) and decreased GFR compared with FHH controls. The severity of tubular atrophy, tubular casts, and interstitial fibrosis increased significantly in Nr4a1(-/-) rats and was accompanied by a large increase in immune cell infiltration, predominantly macrophages and to a lesser extent T cells and B cells. Global transcriptome and network analyses at weeks 8, 16, and 24 identified several proinflammatory genes and pathways differentially regulated between strains. Bone marrow crosstransplantation studies demonstrated that kidney injury in Nr4a1(-/-) rats was almost completely rescued by bone marrow transplanted from FHH controls. In vitro, macrophages isolated from Nr4a1(-/-) rats demonstrated increased immune activation compared with FHH-derived macrophages. In summary, the loss of Nr4a1 in immune cells appears to cause the increased kidney injury and reduced renal function observed in the Nr4a1(-/-) model.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Albuminuria  IMP 12910103; 12910103; 12910103compared to FHHRGD 
Albuminuria  ISONr4a1 (Rattus norvegicus)12910103; 12910103compared to FHHRGD 
chronic kidney disease disease_progressionIMP 12910103; 12910103; 12910103 RGD 
chronic kidney disease disease_progressionISONr4a1 (Rattus norvegicus)12910103; 12910103 RGD 
Hypercholesterolemia  IMP 12910103; 12910103; 12910103compared to FHHRGD 
Hypercholesterolemia  ISONr4a1 (Rattus norvegicus)12910103; 12910103compared to FHHRGD 
Hypertriglyceridemia  IMP 12910103; 12910103; 12910103compared to FHHRGD 
Hypertriglyceridemia  ISONr4a1 (Rattus norvegicus)12910103; 12910103compared to FHHRGD 
proteinuria  IAGP 12910103compared to Crl:SD and compared to FHHRGD 
proteinuria  IAGP 12910103compared to Crl:SDRGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Objects Annotated

Genes (Rattus norvegicus)
Nr4a1  (nuclear receptor subfamily 4, group A, member 1)
Nr4a1m1Mcwi  (nuclear receptor subfamily 4, group A, member 1; mutation 1, Medical College of Wisconsin)

Genes (Mus musculus)
Nr4a1  (nuclear receptor subfamily 4, group A, member 1)

Genes (Homo sapiens)
NR4A1  (nuclear receptor subfamily 4 group A member 1)

Objects referenced in this article
Gene TNF tumor necrosis factor Homo sapiens
Strain FHH Fawn Hooded Hypertensive Rattus norvegicus
Gene Tnf tumor necrosis factor Rattus norvegicus

Additional Information