Some metazoans have evolved the capacity to survive severe oxygen deprivation. The nematode, Caenorhabditis elegans, exposed to anoxia (0 kPa, 0% O 2 ) enters into a recoverable state of suspended animation during all stages of the life cycle. That is, all microscopically observable movement ceases including cell division, developmental progression, feeding, and motility. To understand suspended animation, we compared oxygen-deprived embryos to nontreated embryos in both wild-type and hif-1 mutants. We found that hif-1 mutants survive anoxia, suggesting that the mechanisms for anoxia survival are different from those required for hypoxia. Examination of wild-type embryos exposed to anoxia show that blastomeres arrest in interphase, prophase, metaphase, and telophase but not anaphase. Analysis of the energetic state of anoxic embryos indicated a reversible depression in the ATP to ADP ratio. Given that a decrease in ATP concentrations likely affects a variety of cellular processes, including signal transduction, we compared the phosphorylation state of several proteins in anoxic embryos and normoxic embryos. We found that the phosphorylation state of histone H3 and cell cycle-regulated proteins recognized by the MPM-2 antibody were not detectable in anoxic embryos. Thus, dephosphorylation of specific proteins correlate with the establishment and/or maintenance of a state of anoxia-induced suspended animation.

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There is an emerging concept in clinical nephrology that acute kidney injury (AKI) can initiate chronic kidney disease (CKD). However, potential mechanisms by which this may occur remain elusive. Hence, this study tested the hypotheses that 1) AKI triggers progressive activation of selected proinflammatory genes, 2) there is a relative failure of compensatory anti-inflammatory gene expression, 3) proinflammatory lipid accumulation occurs, 4) these changes correspond with "gene-activating" histone acetylation, and 5) in concert, progressive renal disease results. CD-1 mice were subjected to 30 min of unilateral renal ischemia. Assessments were made 1 day, 1 wk, or 3 wk later. Results were contrasted to those observed in uninjured contralateral kidneys or in kidneys from normal mice. Progressive renal injury occurred throughout the 3-wk postischemic period, as denoted by stepwise increases in neutrophil gelatinase-associated lipocalin gene induction and ongoing histologic damage. By 3 wk postischemia, progressive renal disease was observed (massive tubular dropout; 2/3rds reduction in renal weight). These changes corresponded with progressive increases in proinflammatory cytokine/chemokine gene expression (MCP-1, TNF-α, TGF-β1), a relative failure of anti-inflammatory enzyme/cytokine (heme oxygenase-1; IL-10) upregulation, and progressive renal lipid (cholesterol/triglyceride) loading. Stepwise increases in collagen III mRNA and collagen deposition (Sirius red staining) indicated a progressive profibrotic response. Postischemic dexamethasone treatment significantly preserved renal mass, indicating functional significance of the observed proinflammatory state. Progressive gene-activating H3 acetylation was observed by ELISA, rising from 5% at baseline to 75% at 3 wk. This was confirmed by chromatin immunoprecipitation assay of target genes. In sum, these results provide experimental support for the clinical concept that AKI can trigger CKD, this is partially mediated by progressive postischemic inflammation, ongoing lipid accumulation results (potentially evoking "lipotoxicity"), and increasing histone acetylation at proinflammatory/profibrotic genes may contribute to this self-sustaining injury-promoting state.