Department of Pediatrics, University of Cincinnati College of Medicine, and Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Division of Nephrology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Am J Physiol Renal Physiol. 2020 Mar 1;318(3):F809-F816. doi: 10.1152/ajprenal.00443.2019. Epub 2020 Feb 18.
Pediatric sepsis is a leading cause of morbidity and mortality in children. One of the most common and devastating morbidities is sepsis-related acute kidney injury (AKI). AKI was traditionally thought to be related to low perfusion and acute tubular necrosis. However, little acute tubular necrosis can be found following septic AKI, and little is known about the mechanism of septic AKI. Olfactomedin-4 (OLFM4) is a secreted glycoprotein that marks a subset of neutrophils. Increased expression of OLFM4 in the blood is associated with worse outcomes in sepsis. Here, we investigated a pediatric model of murine sepsis using murine pups to investigate the mechanisms of OLFM4 in sepsis. When sepsis was induced in murine pups, survival was significantly increased in OLFM4-null pups. Immunohistochemistry at 24 h after the induction of sepsis demonstrated increased expression of OLFM4 in the kidney, which was localized to the loop of Henle. Renal cell apoptosis and plasma creatinine were significantly increased in wild-type versus OLFM4-null pups. Finally, bone marrow transplant suggested that increased OLFM4 in the kidney reflects local production rather than filtered from the plasma. These results demonstrate renal expression of OLFM4 for the first time and suggest that a kidney-specific mechanism may contribute to survival differences in OLFM4-null animals.
儿科脓毒症是儿童发病率和死亡率的主要原因。最常见和最具破坏性的并发症之一是脓毒症相关的急性肾损伤（AKI）。AKI 传统上被认为与低灌注和急性肾小管坏死有关。然而，在脓毒性 AKI 后很少能发现急性肾小管坏死，对脓毒性 AKI 的发病机制知之甚少。嗅鞘蛋白 4（OLFM4）是一种分泌糖蛋白，可标记一组中性粒细胞。血液中 OLFM4 的表达增加与脓毒症的预后不良有关。在这里，我们使用幼鼠研究了小儿脓毒症模型，以研究 OLFM4 在脓毒症中的作用机制。当在幼鼠中诱导脓毒症时，OLFM4 缺失幼鼠的存活率显著提高。脓毒症诱导后 24 小时的免疫组织化学显示，肾脏中 OLFM4 的表达增加，主要定位于 Henle 袢。与 OLFM4 缺失幼鼠相比，野生型幼鼠的肾细胞凋亡和血浆肌酐显著增加。最后，骨髓移植表明，肾脏中 OLFM4 的增加反映了局部产生，而不是从血浆中过滤而来。这些结果首次证明了肾脏中 OLFM4 的表达，并表明肾脏特异性机制可能导致 OLFM4 缺失动物的生存差异。
