BRG1 Increases Transcription of Proinflammatory Genes in Renal Ischemia

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American Society of Nephrology

RESUMO

Acute kidney injury stimulates renal production of inflammatory mediators, including TNF-α and monocyte chemoattractant protein 1 (MCP-1). These responses reflect, in part, injury-induced transcription of proinflammatory genes by proximal tubule cells. Because of the compact structure of chromatin, a series of events at specified loci remodel chromatin to provide access for transcription factors and RNA polymerase II (Pol II). Here, we examined the role of Brahma-related gene-1 (BRG1), a chromatin remodeling enzyme, in the transcription of TNF-α and MCP-1 in response to renal ischemia. Two hours after renal ischemic injury in mice, renal TNF-α and MCP-1 mRNA increased and remained elevated for at least 1 wk. Matrix chromatin immunoprecipitation assays revealed sustained increases in Pol II at these genes, suggesting that the elevated mRNA levels were, at least in part, transcriptionally mediated. The profile of BGR1 binding to the genes encoding TNF-α and MCP-1 resembled Pol II recruitment. Knockdown of BRG1 by small interfering RNA blocked an ATP depletion–induced increase in TNF-α and MCP-1 transcription in a human proximal tubule cell line; this effect was associated with decreased recruitment of BRG1 and Pol II to these genes. In conclusion, BRG1 promotes increased transcription of TNF-α and MCP-1 by the proximal tubule in response to renal ischemia.

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