Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., Seattle, WA 98109, USA.
Am J Physiol Renal Physiol. 2011 Dec;301(6):F1334-45. doi: 10.1152/ajprenal.00431.2011. Epub 2011 Sep 14.
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.
在临床肾脏病学中有一个新兴概念，即急性肾损伤 (AKI) 可引发慢性肾脏病 (CKD)。然而，其发生的潜在机制仍不明确。因此，本研究旨在验证以下假设：1）AKI 引发选定促炎基因的渐进性激活；2）抗炎基因表达的代偿性相对失败；3）促炎脂质蓄积；4）这些变化与“基因激活”组蛋白乙酰化相对应；5）协同作用导致进行性肾脏疾病的发生。CD-1 小鼠经历单侧肾脏缺血 30 分钟。在 1 天、1 周或 3 周后进行评估。结果与未受伤的对侧肾脏或正常小鼠肾脏的结果进行对比。在整个缺血后 3 周期间，渐进性肾损伤发生，表现为中性粒细胞明胶酶相关脂质运载蛋白基因诱导的逐步增加和持续的组织学损伤。在缺血后 3 周时，观察到进行性肾脏疾病（大量肾小管脱落；肾脏重量减少 2/3）。这些变化与促炎细胞因子/趋化因子基因表达的逐渐增加（MCP-1、TNF-α、TGF-β1）、抗炎酶/细胞因子（血红素加氧酶-1；IL-10）上调的相对失败以及渐进性肾脏脂质（胆固醇/甘油三酯）负荷相对应。III 型胶原 mRNA 和胶原沉积（天狼星红染色）的逐步增加表明进行性纤维化反应。缺血后给予地塞米松治疗可显著保存肾脏质量，表明观察到的促炎状态具有功能意义。通过 ELISA 观察到进行性基因激活 H3 乙酰化，从基线的 5%上升到 3 周时的 75%。通过靶向基因的染色质免疫沉淀测定证实了这一点。总之，这些结果为 AKI 可引发 CKD 的临床概念提供了实验支持，这部分是通过渐进性缺血后炎症、持续脂质蓄积的结果（可能引发“脂毒性”）以及促炎/纤维化基因的组蛋白乙酰化增加来介导的，这可能有助于维持这种自促损伤状态。
