Wijnsma Kioa L, Veissi Susan T, de Wijs Sem, van der Velden Thea, Volokhina Elena B, Wagener Frank A D T G, van de Kar Nicole C A J, van den Heuvel L P
Department of Pediatric Nephrology, Radboud Institute for Molecular Life Sciences, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, Netherlands.
Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
Front Immunol. 2020 Dec 22;11:547406. doi: 10.3389/fimmu.2020.547406. eCollection 2020.
Shiga-toxin (Stx)-producing hemolytic-uremic syndrome (STEC-HUS) is one of the most common causes of acute kidney injury in children. Stx-mediated endothelial injury initiates the cascade leading to thrombotic microangiopathy (TMA), still the exact pathogenesis remains elusive. Interestingly, there is wide variability in clinical presentation and outcome. One explanation for this could be the enhancement of TMA through other factors. We hypothesize that heme, as released during extensive hemolysis, contributes to the etiology of TMA. Plasma levels of heme and its scavenger hemopexin and degrading enzyme heme-oxygenase-1 (HO-1) were measured in 48 STEC-HUS patients. Subsequently, the effect of these disease-specific heme concentrations, in combination with Stx, was assessed on primary human glomerular microvascular endothelial cells (HGMVECs). Significantly elevated plasma heme levels up to 21.2 µM were found in STEC-HUS patients compared to controls and were inversely correlated with low or depleted plasma hemopexin levels (R -0.74). Plasma levels of HO-1 are significantly elevated compared to controls. Interestingly, especially patients with high heme levels (n = 12, heme levels above 75 quartile range) had high plasma HO-1 levels with median of 332.5 (86-720) ng/ml (p = 0.008). Furthermore, heme is internalized leading to a significant increase in reactive oxygen species production and stimulated both nuclear translocation of NF-κB and increased levels of its target gene (tissue factor). In conclusion, we are the first to show elevated heme levels in patients with STEC-HUS. These increased heme levels mediate endothelial injury by promoting oxidative stress and a pro-inflammatory and pro-thrombotic state. Hence, heme may be a contributing and driving factor in the pathogenesis of STEC-HUS and could potentially amplify the cascade leading to TMA.
产志贺毒素（Stx）的溶血尿毒综合征（STEC-HUS）是儿童急性肾损伤最常见的病因之一。Stx介导的内皮损伤引发了导致血栓性微血管病（TMA）的级联反应，但其确切发病机制仍不清楚。有趣的是，临床表现和预后存在很大差异。对此的一种解释可能是其他因素增强了TMA。我们推测，在广泛溶血过程中释放的血红素促成了TMA的病因。对48例STEC-HUS患者的血浆血红素及其清除剂血红素结合蛋白和降解酶血红素加氧酶-1（HO-1）水平进行了检测。随后，评估了这些疾病特异性血红素浓度与Stx联合作用对原代人肾小球微血管内皮细胞（HGMVECs）的影响。与对照组相比，STEC-HUS患者的血浆血红素水平显著升高，最高可达21.2 μM，且与血浆血红素结合蛋白水平低或耗尽呈负相关（R -0.74）。与对照组相比，血浆HO-1水平显著升高。有趣的是，尤其是血红素水平高的患者（n = 12，血红素水平高于四分位数范围的75%）血浆HO-1水平高，中位数为332.5（86-720）ng/ml（p = 0.008）。此外，血红素被内化导致活性氧生成显著增加，并刺激了NF-κB的核转位及其靶基因（组织因子）水平的升高。总之，我们首次发现STEC-HUS患者的血红素水平升高。这些升高的血红素水平通过促进氧化应激以及促炎和促血栓形成状态来介导内皮损伤。因此，血红素可能是STEC-HUS发病机制中的一个促成和驱动因素，并可能潜在地放大导致TMA的级联反应。
