Orosomucoid 1 is involved in the development of chronic allograft rejection after kidney transplantation
Orosomucoid 1 is involved in the development of chronic allograft rejection after kidney transplantation
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DOI：
10.1093/intimm/dxaa003
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发表时间：
2020-05-01
影响因子：
4.4
通讯作者：
Murakami, Masaaki
中科院分区：
文献类型：
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作者：
Higuchi, Haruka;Kamimura, Daisuke;Murakami, Masaaki
慢性同种异体移植排斥反应是长期同种异体移植失败的最常见原因。一个原因是目前对慢性同种异体移植排斥反应的诊断和治疗方法非常有限。我们在这里表明，肾移植中增强的核因子-kappaB信号有助于慢性主动抗体介导的排斥反应(CAAMR)，这是慢性移植肾排斥反应的主要病理机制。此外，我们还发现尿orosomucid 1(ORM1)是CAAMR的候选标记分子和治疗靶点。的确，经病理诊断为CAAMR的肾移植受者的尿液ORM1浓度显著高于组织学正常、钙调神经磷酸酶抑制剂毒性、间质纤维化和肾小管萎缩的受者。此外，我们还发现，与非CAAMR肾活检标本相比，CAAMR肾活检标本在肾小管上皮细胞中表达更多的ORM1，并具有更高的NF-kappaB和STAT3活性。在原代肾小管上皮细胞中，细胞因子介导的NF-kappaB和STAT3激活后，ORM1的产生一直被诱导。ORM1功能缺失和功能增强分别抑制和促进了核因子-kappaB的激活。最后，在体内，ORM1促进了核因子-kappaB介导的炎症发展。这些结果表明，肾移植后肾移植慢性排斥反应的发生可能与移植肾中依赖于核因子kappaB和STAT3的途径有关，ORM1是肾移植慢性排斥反应的无创性候选生物标志物和可能的治疗靶点。
Chronic allograft rejection is the most common cause of long-term allograft failure. One reason is that current diagnostics and therapeutics for chronic allograft rejection are very limited. We here show that enhanced NF kappa B signaling in kidney grafts contributes to chronic active antibody-mediated rejection (CAAMR), which is a major pathology of chronic kidney allograft rejections. Moreover, we found that urinary orosomucoid 1 (ORM1) is a candidate marker molecule and therapeutic target for CAAMR. Indeed, urinary ORM1 concentration was significantly higher in kidney transplant recipients pathologically diagnosed with CAAMR than in kidney transplant recipients with normal histology, calcineurin inhibitor toxicity, or interstitial fibrosis and tubular atrophy. Additionally, we found that kidney biopsy samples with CAAMR expressed more ORM1 and had higher NF kappa B and STAT3 activation in tubular cells than samples from non-CAAMR samples. Consistently, ORM1 production was induced after cytokine-mediated NF kappa B and STAT3 activation in primary kidney tubular cells. The loss- and gain-of-function of ORM1 suppressed and promoted NF kappa B activation, respectively. Finally, ORM1-enhanced NF kappa B-mediated inflammation development in vivo. These results suggest that an enhanced NF kappa B-dependent pathway following NF kappa B and STAT3 activation in the grafts is involved in the development of chronic allograft rejection after kidney transplantation and that ORM1 is a non-invasive candidate biomarker and possible therapeutic target for chronic kidney allograft rejection.