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Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 J+Immunol 2015 ; 194 (10): 4705-16 Nephropedia Template TP
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Macrophage epoxygenase determines a pro-fibrotic transcriptome signature #MMPMID25840911
J Immunol 2015[May]; 194 (10): 4705-16 PMID25840911show ga
Epoxygenases belong to the cytochrome P450 family and they generate epoxyeicosatrienoic acids (EETs) known to have anti-inflammatory effects but little is known about their role in macrophage function. By high-throughput sequencing of RNA (RNA-seq) in primary macrophages derived from rodents and humans, we establish the relative expression of epoxygenases in these cells. Zinc-finger nuclease-mediated targeted gene deletion of the major rat macrophage epoxygenase Cyp2j4 (orthologue of human CYP2J2), resulted in reduced EET synthesis. Cyp2j4?/? macrophages have relatively increased PPAR? levels and show a pro-fibrotic transcriptome, displaying over-expression of a specific subset of genes (260 transcripts) primarily involved in extracellular matrix, with fibronectin being the most abundantly expressed transcript. Fibronectin expression is under the control of epoxygenase activity in human and rat primary macrophages. In keeping with the in vitro findings, Cyp2j4?/? rats show up-regulation of type I collagen following unilateral ureter obstruction (UUO) of the kidney and quantitative proteomics analysis (LC-MS/MS) showed increased renal type I collagen and fibronectin protein abundance resulting from experimentally induced crescentic glomerulonephritis in these rats. Taken together, these results identify the rat epoxygenase Cyp2j4 as a determinant of a pro-fibrotic macrophage transcriptome that could have implications in various inflammatory conditions depending on macrophage function.