{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T14:09:34Z","timestamp":1773410974503,"version":"3.50.1"},"reference-count":49,"publisher":"American Physiological Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Renal Physiology"],"published-print":{"date-parts":[[2010,3]]},"abstract":"<jats:p> Rhabdomyolysis (Fe)-induced acute renal failure (ARF) causes renal inflammation, and, with repetitive insults, progressive renal failure can result. To gain insights into these phenomena, we assessed the impact of a single episode of glycerol-induced rhabdomyolysis on proinflammatory\/profibrotic [TNF-\u03b1, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-\u03b21 (TGF-\u03b21)] gene expression and the time course of these changes. CD-1 mice were studied 1\u20137 days after glycerol injection. Normal mice served as controls. RNA polymerase II (Pol II) binding to the TNF-\u03b1, MCP-1, and TGF-\u03b21 genes, \u201cgene-activating\u201d histone modifications [histone 3 lysine 4 (H3K4) trimethylation (H3K4m3) and histone 2 variant H2A.Z], and cognate mRNA levels were assessed. Results were contrasted to changes in anti-inflammatory heme oxygenase-1 (HO-1). Glycerol produced severe ARF (blood urea nitrogen \u223c150\u2013180 mg\/dl) followed by marked improvement by day 7 (blood urea nitrogen \u223c40 mg\/dl). Early increases in TNF-\u03b1, MCP-1, and TGF-\u03b21 mRNAs, Pol II gene binding, and H3K4m3\/H2A.Z levels were observed. These progressed with time, despite resolution of azotemia. Comparable early HO-1 changes were observed. However, HO-1 mRNA normalized by day 7, and progressive Pol II binding\/histone alterations did not occur. Fe-mediated injury to cultured proximal tubule (HK-2) cells recapitulated these in vivo results. Hence, this in vitro model was used for mechanistic assessments. On the basis of these studies, it was determined that 1) the H3K4m3\/H2A.Z increases are early events (i.e., they precede mRNA increases), 2) subsequent mRNA elevations reflect transcription, not mRNA stabilization (actinomycin D assessments), and 3) increased transcription, per se, helps sustain elevated H2A.Z levels. We conclude that 1) Fe\/glycerol-induced tubular injury causes sustained proinflammatory gene activation, 2) decreasing HO-1 expression, as reflected by mRNA levels, may facilitate this proinflammatory state, and 3) gene-activating histone modifications are early injury events and progressively increase at selected proinflammatory genes. Thus they may help sustain a proinflammatory state, despite resolving ARF. <\/jats:p>","DOI":"10.1152\/ajprenal.00683.2009","type":"journal-article","created":{"date-parts":[[2009,12,24]],"date-time":"2009-12-24T02:45:46Z","timestamp":1261622746000},"page":"F827-F837","source":"Crossref","is-referenced-by-count":31,"title":["Progressive histone alterations and proinflammatory gene activation: consequences of heme protein\/iron-mediated proximal tubule injury"],"prefix":"10.1152","volume":"298","author":[{"given":"Richard A.","family":"Zager","sequence":"first","affiliation":[{"name":"Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington, Seattle, Washington"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali C. 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