RGD Reference Report - Renal ischemia-induced cholesterol loading: transcription factor recruitment and chromatin remodeling along the HMG CoA reductase gene. - Rat Genome Database

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Renal ischemia-induced cholesterol loading: transcription factor recruitment and chromatin remodeling along the HMG CoA reductase gene.

Authors: Naito, M  Bomsztyk, K  Zager, RA 
Citation: Naito M, etal., Am J Pathol. 2009 Jan;174(1):54-62. doi: 10.2353/ajpath.2009.080602. Epub 2008 Dec 18.
RGD ID: 7242184
Pubmed: PMID:19095962   (View Abstract at PubMed)
PMCID: PMC2631318   (View Article at PubMed Central)
DOI: DOI:10.2353/ajpath.2009.080602   (Journal Full-text)

Acute kidney injury evokes renal tubular cholesterol synthesis. However, the factors during acute kidney injury that regulate HMG CoA reductase (HMGCR) activity, the rate-limiting step in cholesterol synthesis, have not been defined. To investigate these factors, mice were subjected to 30 minutes of either unilateral renal ischemia or sham surgery. After 3 days, bilateral nephrectomy was performed and cortical tissue extracts were prepared. The recruitment of RNA polymerase II (Pol II), transcription factors (SREBP-1, SREBP-2, NF-kappaB, c-Fos, and c-Jun), and heat shock proteins (HSP-70 and heme oxygenase-1) to the HMGCR promoter and transcription region (start/end exons) were assessed by Matrix ChIP assay. HMGCR mRNA, protein, and cholesterol levels were determined. Finally, histone modifications at HMGCR were assessed. Ischemia/reperfusion (I/R) induced marked cholesterol loading, which corresponded with elevated Pol II recruitment to HMGCR and increased expression levels of both HMGCR protein and mRNA. I/R also induced the binding of multiple transcription factors (SREBP-1, SREBP-2, c-Fos, c-Jun, NF-kappaB) and heat shock proteins to the HMGCR promoter and transcription regions. Significant histone modifications (increased H3K4m3, H3K19Ac, and H2A.Z variant) at these loci were also observed but were not identified at either the 5' and 3' HMGCR flanking regions (+/-5000 bps) or at negative control genes (beta-actin and beta-globin). In conclusion, I/R activates the HMGCR gene via multiple stress-activated transcriptional and epigenetic pathways, contributing to renal cholesterol loading.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Kidney Reperfusion Injury  ISOFos (Mus musculus)7242184; 7242184 RGD 
Kidney Reperfusion Injury  IEP 7242184 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Fos  (Fos proto-oncogene, AP-1 transcription factor subunit)

Genes (Mus musculus)
Fos  (FBJ osteosarcoma oncogene)

Genes (Homo sapiens)
FOS  (Fos proto-oncogene, AP-1 transcription factor subunit)


Additional Information