Published online before print December 18, 2008

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(American Journal of Pathology. 2009;174:54-62.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080602

Renal Ischemia-Induced Cholesterol Loading

Transcription Factor Recruitment and Chromatin Remodeling along the HMG CoA Reductase Gene

Masayo Naito^*, Karol Bomsztyk and Richard A. Zager^*

From the Fred Hutchinson Cancer Research Center^*, Seattle; and the Department of Medicine, University of Washington, Seattle, Washington

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-B, 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-B) 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 (β-actin and β-globin). In conclusion, I/R activates the HMGCR gene via multiple stress-activated transcriptional and epigenetic pathways, contributing to renal cholesterol loading.

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