Haptoglobin attenuates hemoglobin-induced heme oxygenase-1 in renal proximal tubule cells and kidneys of a mouse model of sickle cell disease
Haptoglobin attenuates hemoglobin-induced heme oxygenase-1 in renal proximal tubule cells and kidneys of a mouse model of sickle cell disease
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DOI：
10.1016/j.bcmd.2014.12.001
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发表时间：
2015-03-01
影响因子：
2.3
通讯作者：
Alayash, Abdu I.
中科院分区：
文献类型：
--
作者：
Chintagari, Narendranath Reddy;Julia Nguyen;Alayash, Abdu I.
镰状细胞病(SCD)是一种遗传性溶血性疾病，以慢性溶血、氧化应激、血管闭塞和终末器官损害为特征。溶血会释放有毒的无细胞血红蛋白(Hb)进入循环。在生理条件下，血浆Hb与结合珠蛋白(Hp)结合形成Hb-Hp二聚体。二聚体与巨噬细胞上的CD163受体结合，进一步内化和降解。然而，在SCD患者中，血浆Hp被耗尽，游离Hb主要通过肾脏近端小管被清除。血浆中过多的游离Hb使患者容易发生肾脏损害。我们假设给予外源性幽门螺杆菌可以减少Hb介导的肾损害。为了验证这一假说，人肾小管上皮细胞(HK-2)暴露于HBA(50 MU血红素)24小时后，HBA增加了HO-1的表达，HO-1是一种降解血红素的酶，降低了血红素介导的氧化毒性，并提供了细胞保护作用。同样，输注HBA(32mU血红素/公斤)可诱导SCD小鼠肾脏HO-1表达。免疫组织化学证实HO-1在肾脏近端小管表达增加。外源性HP在体外和SCD小鼠体内均可减弱HBA诱导的HO-1的表达。我们的结果表明，Hb介导的氧化毒性可能是SCD肾脏损害的原因之一，而Hp治疗可降低溶血后肾脏中的血红素/铁毒性。由爱思唯尔公司出版。
Sickle cell disease (SCD), a hereditary hemolytic disorder is characterized by chronic hemolysis, oxidative stress, vaso-occlusion and end-organ damage. Hemolysis releases toxic cell-free hemoglobin (Hb) into circulation. Under physiologic conditions, plasma Hb binds to haptoglobin (Hp) and forms Hb-Hp dimers. The dimers bind to CD163 receptors on macrophages for further internalization and degradation. However, in SCD patients plasma Hp is depleted and free Hb is cleared primarily by proximal tubules of kidneys. Excess free Hb in plasma predisposes patients to renal damage. We hypothesized that administration of exogenous Hp reduces Hb-mediated renal damage. To test this hypothesis, human renal proximal tubular cells (HK-2) were exposed to HbA (50 mu M heme) for 24 h. HbA increased the expression of heme oxygenase-1 (HO-1), an enzyme which degrades heme, reduces heme-mediated oxidative toxicity, and confers cytoprotection. Similarly, infusion of HbA (32 mu M heme/kg) induced HO-1 expression in kidneys of SCD mice. Immunohistochemistry confirmed the increased HO-1 expression in the proximal tubules of the kidney. Exogenous Hp attenuated the HbA-induced HO-1 expression in vitro and in SCD mice. Our results suggest that Hb-mediated oxidative toxicity may contribute to renal damage in SCD and that Hp treatment reduces heme/iron toxicity in the kidneys following hemolysis. Published by Elsevier Inc.