Role of interaction of mannan-binding protein with meprins at the initial step of complement activation in ischemia/reperfusion injury to mouse kidney
Role of interaction of mannan-binding protein with meprins at the initial step of complement activation in ischemia/reperfusion injury to mouse kidney
复制标题
DOI：
10.1093/glycob/cwr107
复制
发表时间：
2012-01-01
期刊：
影响因子：
4.3
通讯作者：
Kawasaki, Toshisuke
中科院分区：
文献类型：
--
作者：
Hirano, Makoto;Ma, Bruce Y.;Kawasaki, Toshisuke
缺血/再灌注（I/R）是急性肾功能衰竭的重要原因。近年来的研究表明，由甘露聚糖结合蛋白（MBP）介导的补体系统在缺血性急性肾功能衰竭的发病机制中起着关键作用，MBP是一种识别甘露糖、岩藻糖和N-乙酰氨基葡萄糖残基的C型血清凝集素。MBP通过MBP凝集素途径引起补体活化，并且所得补体组分C3 b积聚在肾I/R操作的小鼠肾中的肾近端小管的刷状缘上。然而，补体激活的初始步骤尚未被广泛研究。我们先前鉴定了meprins α和β，高度糖基化的锌金属蛋白酶，定位于肾脏近端小管作为内源性MBP配体。在本研究中，我们证明，血清型MBP（S-MBP）和C3 b的共同定位与meprins的皮质和髓质在肾I/R手术小鼠肾脏。在I/R手术小鼠肾脏中，S-MBP被指示与体内的meprins相互作用，并且被示出通过与meprins的体外相互作用来启动补体激活。本研究结果提示，S-MBP与meprins结合后，通过凝集素途径激活补体，可能导致肾移植I/R后急性肾功能衰竭和失血性休克。
Ischemia/reperfusion (I/R) is an important cause of acute renal failure. Recent studies have shown that the complement system mediated by the mannan-binding protein (MBP), which is a C-type serum lectin recognizing mannose, fucose and N-acetylglucosamine residues, plays a critical role in the pathogenesis of ischemic acute renal failure. MBP causes complement activation through the MBP lectin pathway and a resulting complement component, C3b, is accumulated on the brush borders of kidney proximal tubules in a renal I/R-operated mouse kidney. However, the initial step of the complement activation has not been studied extensively. We previously identified both meprins alpha and beta, highly glycosylated zinc metalloproteases, localized on kidney proximal tubules as endogenous MBP ligands. In the present study, we demonstrated that serum-type MBP (S-MBP) and C3b were co-localized with meprins on both the cortex and the medulla in the renal I/R-operated mouse kidney. S-MBP was indicated to interact with meprins in vivo in the I/R-operated mouse kidney and was shown to initiate the complement activation through the interaction with meprins in vitro. Taken together, the present study strongly suggested that the binding of S-MBP to meprins triggers the complement activation through the lectin pathway and may cause the acute renal failure due to I/R on kidney transplantation and hemorrhagic shock.