Department of Chemistry and Biochemistry, Miami University , Oxford, Ohio.
Department of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, University of Cincinnati , Cincinnati, Ohio.
Am J Physiol Renal Physiol. 2018 Oct 1;315(4):F1159-F1173. doi: 10.1152/ajprenal.00500.2017. Epub 2018 Jul 11.
Acute kidney injury can be caused by multiple factors, including sepsis, respiratory failure, heart failure, trauma, or nephrotoxic medications, among others. Here, a mouse model was used to investigate potential urinary metabolic biomarkers of hypoxia-induced AKI. Urine metabolic profiles of 48 Swiss Webster mice were assessed using nuclear magnetic resonance spectroscopy (NMR) for 7 days following 72 h exposure to a hypoxic 6.5% oxygen environment. Histological analyses indicated a lack of gross nephron structural changes in the aftermath of hypoxia. Immunohistochemical (IHC) analyses, however, indicated elevated expression of protein injury biomarkers in distal and proximal tubules but not glomeruli. Kidney injury molecule-1 levels peaked in distal tubules at 72 h and were still increasing in proximal tubules at 7 days posthypoxia, whereas cystatin C levels were elevated at 24 h but decreased thereafter, and were elevated and still increasing in proximal tubules at 7 days posthypoxia. Neutrophil gelatinase-associated lipocalin levels were modestly elevated from 24 h to 7 days posthypoxia. NMR-based metabolic profiling revealed that urine metabolites involved in energy metabolism and associated biosynthetic pathways were initially decreased at 24 h posthypoxia, consistent with metabolic suppression as a mechanism for cell survival, but were significantly elevated at 48 and 72 h posthypoxia, indicating a burst in organism metabolism associated with reactivation of cellular energetics during recovery after cessation of hypoxia and return to a normoxic environment. The IHC results indicated that kidney injury persists long after plasma and urine biomarkers of hypoxia return to normal values.
急性肾损伤可由多种因素引起，包括败血症、呼吸衰竭、心力衰竭、创伤或肾毒性药物等。在这里，使用小鼠模型来研究缺氧诱导的 AKI 的潜在尿代谢生物标志物。在缺氧 6.5%氧气环境中暴露 72 小时后，通过核磁共振波谱（NMR）评估 48 只瑞士 Webster 小鼠的尿液代谢谱 7 天。组织学分析表明缺氧后肾小球结构没有明显的大体变化。然而，免疫组织化学（IHC）分析表明，远曲小管和近曲小管中的蛋白质损伤生物标志物表达升高，但肾小球中没有。肾损伤分子-1 水平在缺氧后 72 小时时在远曲小管中达到峰值，并且在缺氧后 7 天仍在近曲小管中增加，而胱抑素 C 水平在 24 小时时升高，但此后降低，并且在缺氧后 7 天在近曲小管中升高并仍在增加。中性粒细胞明胶酶相关脂质运载蛋白水平在缺氧后 24 小时至 7 天适度升高。基于 NMR 的代谢谱分析显示，与能量代谢和相关生物合成途径相关的尿液代谢物在缺氧后 24 小时最初降低，这与细胞存活的代谢抑制机制一致，但在缺氧后 48 小时和 72 小时显著升高，表明在停止缺氧并返回正常氧环境后细胞能量恢复期间，与细胞代谢重新激活相关的生物体代谢急剧增加。IHC 结果表明，在血浆和尿液缺氧生物标志物恢复正常值后很长一段时间内，肾脏损伤仍然存在。
