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

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
FHH-Nr4a1m1McwiRatAlbuminuria  IMP compared to FHHRGD 
NR4A1HumanAlbuminuria  ISONr4a1 (Rattus norvegicus)compared to FHHRGD 
Nr4a1RatAlbuminuria  IMP compared to FHHRGD 
Nr4a1MouseAlbuminuria  ISONr4a1 (Rattus norvegicus)compared to FHHRGD 
Nr4a1m1McwiRatAlbuminuria  IMP compared to FHHRGD 
FHH-Nr4a1m1McwiRatchronic kidney disease disease_progressionIMP  RGD 
NR4A1Humanchronic kidney disease disease_progressionISONr4a1 (Rattus norvegicus) RGD 
Nr4a1Ratchronic kidney disease disease_progressionIMP  RGD 
Nr4a1Mousechronic kidney disease disease_progressionISONr4a1 (Rattus norvegicus) RGD 
Nr4a1m1McwiRatchronic kidney disease disease_progressionIMP  RGD 
FHH-Nr4a1m1McwiRatHypercholesterolemia  IMP compared to FHHRGD 
NR4A1HumanHypercholesterolemia  ISONr4a1 (Rattus norvegicus)compared to FHHRGD 
Nr4a1RatHypercholesterolemia  IMP compared to FHHRGD 
Nr4a1MouseHypercholesterolemia  ISONr4a1 (Rattus norvegicus)compared to FHHRGD 
Nr4a1m1McwiRatHypercholesterolemia  IMP compared to FHHRGD 
FHH-Nr4a1m1McwiRatHypertriglyceridemia  IMP compared to FHHRGD 
NR4A1HumanHypertriglyceridemia  ISONr4a1 (Rattus norvegicus)compared to FHHRGD 
Nr4a1RatHypertriglyceridemia  IMP compared to FHHRGD 
Nr4a1MouseHypertriglyceridemia  ISONr4a1 (Rattus norvegicus)compared to FHHRGD 
Nr4a1m1McwiRatHypertriglyceridemia  IMP compared to FHHRGD 
FHH.PCK-(D9Rat35-D9Rat70)/McwiRatproteinuria  IAGP compared to Crl:SD and compared to FHHRGD 
PCK-Pkhd1pck/CrljCrlRatproteinuria  IAGP compared to Crl:SDRGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Nr4a1Ratabnormal renal glomerular filtration  IMP  RGD 
Nr4a1Ratalbuminuria  IMP  RGD 
FHH-Nr4a1m1McwiRatdecreased body weight  IMP compared to FHHRGD 
Nr4a1Ratdecreased body weight  IMP compared to FHHRGD 
Nr4a1m1McwiRatdecreased body weight  IMP compared to FHHRGD 
FHH-Nr4a1m1McwiRatdecreased creatinine clearance  IMP compared to FHHRGD 
Nr4a1Ratdecreased creatinine clearance  IMP compared to FHHRGD 
Nr4a1m1McwiRatdecreased creatinine clearance  IMP compared to FHHRGD 
FHH-Nr4a1m1McwiRatdecreased renal glomerular filtration rate  IMP compared to FHHRGD 
Nr4a1Ratdecreased renal glomerular filtration rate  IMP  RGD 
Nr4a1m1McwiRatdecreased renal glomerular filtration rate  IMP  RGD 
FHH-Nr4a1m1McwiRatincreased blood urea nitrogen level  IMP compared to FHHRGD 
FHH.PCK-(D9Rat35-D9Rat70)/McwiRatincreased blood urea nitrogen level  IAGP compared to FHHRGD 
Nr4a1Ratincreased blood urea nitrogen level  IMP compared to FHHRGD 
Nr4a1m1McwiRatincreased blood urea nitrogen level  IMP compared to FHHRGD 
PCK-Pkhd1pck/CrljCrlRatincreased blood urea nitrogen level  IAGP compared to Crl:SD and compared to FHHRGD 
FHH.PCK-(D9Rat35-D9Rat70)/McwiRatincreased circulating creatinine level  IAGP compared to FHHRGD 
PCK-Pkhd1pck/CrljCrlRatincreased circulating creatinine level  IAGP compared to Crl:SD and compared to FHHRGD 
FHH-Nr4a1m1McwiRatincreased circulating triglyceride level  IMP compared to FHHRGD 
Nr4a1Ratincreased circulating triglyceride level  IMP compared to FHHRGD 
Nr4a1m1McwiRatincreased circulating triglyceride level  IMP compared to FHHRGD 
FHH-Nr4a1m1McwiRatincreased kidney weight  IMP compared to FHHRGD 
Nr4a1Ratincreased kidney weight  IMP compared to FHHRGD 
Nr4a1m1McwiRatincreased kidney weight  IMP compared to FHHRGD 
PCK-Pkhd1pck/CrljCrlRatincreased kidney weight  IAGP compared to Crl:SD and compared to FHHRGD 
PCK-Pkhd1pck/CrljCrlRatincreased mean systemic arterial blood pressure  IAGP compared to Crl:SDRGD 
PCK-Pkhd1pck/CrljCrlRatkidney cyst  IAGP compared to Crl:SD and compared to FHHRGD 
FHH-Nr4a1m1McwiRatrenal interstitial fibrosis  IMP compared to FHHRGD 
Nr4a1Ratrenal interstitial fibrosis  IMP compared to FHHRGD 
Nr4a1m1McwiRatrenal interstitial fibrosis  IMP compared to FHHRGD 

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