1 Department of Surgery, National Taiwan University Hospital , Taipei, Taiwan .
Antioxid Redox Signal. 2014 Mar 10;20(8):1181-94. doi: 10.1089/ars.2013.5366. Epub 2013 Sep 17.
Free iron plays an important role in the pathogenesis of acute kidney injury (AKI) via the formation of hydroxyl radicals. Systemic iron homeostasis is controlled by the hemojuvelin-hepcidin-ferroportin axis in the liver, but less is known about this role in AKI.
By proteomics, we identified a 42 kDa soluble hemojuvelin (sHJV), processed by furin protease from membrane-bound hemojuvelin (mHJV), in the urine during AKI after cardiac surgery. Biopsies from human and mouse specimens with AKI confirm that HJV is extensively increased in renal tubules. Iron overload enhanced the expression of hemojuvelin-hepcidin signaling pathway. The furin inhibitor (FI) decreases furin-mediated proteolytic cleavage of mHJV into sHJV and augments the mHJV/sHJV ratio after iron overload with hypoxia condition. The FI could reduce renal tubule apoptosis, stabilize hypoxic induced factor-1, prevent the accumulation of iron in the kidney, and further ameliorate ischemic-reperfusion injury. mHJV is associated with decreasing total kidney iron, secreting hepcidin, and promoting the degradation of ferroportin at AKI, whereas sHJV does the opposite.
This study suggests the ratio of mHJV/sHJV affects the iron deposition during acute kidney injury and sHJV could be an early biomarker of AKI.
Our findings link endogenous HJV inextricably with renal iron homeostasis for the first time, add new significance to early predict AKI, and identify novel therapeutic targets to reduce the severity of AKI using the FI.
游离铁通过形成羟自由基在急性肾损伤（AKI）发病机制中起重要作用。铁在体内的稳态由肝脏中的血红素结合蛋白-铁调素-亚铁转运蛋白轴控制，但在 AKI 中对这一作用知之甚少。
通过蛋白质组学，我们在心脏手术后 AKI 期间的尿液中鉴定出一种 42 kDa 的可溶性血红素结合蛋白（sHJV），它是由膜结合血红素结合蛋白（mHJV）中的弗林蛋白酶加工而成。来自 AKI 人类和小鼠标本的活检证实，HJV 在肾小管中广泛增加。铁过载增强了血红素结合蛋白-铁调素信号通路的表达。弗林抑制剂（FI）减少弗林介导的 mHJV 蛋白水解切割成 sHJV，并在铁过载和缺氧条件下增加 mHJV/sHJV 比值。FI 可以减少肾小管细胞凋亡，稳定缺氧诱导因子-1，防止铁在肾脏中的积累，并进一步改善缺血再灌注损伤。mHJV 与 AKI 时总肾铁减少、铁调素分泌和促进亚铁转运蛋白降解有关，而 sHJV 则相反。
本研究表明 mHJV/sHJV 的比值影响急性肾损伤期间的铁沉积，sHJV 可能是 AKI 的早期生物标志物。
我们的研究结果首次将内源性 HJV 与肾脏铁稳态紧密联系起来，为早期预测 AKI 增添了新的意义，并确定了使用 FI 减少 AKI 严重程度的新治疗靶点。
