Unrestricted C3 activation occurs in Crry-deficient kidneys and rapidly leads to chronic renal failure
Unrestricted C3 activation occurs in Crry-deficient kidneys and rapidly leads to chronic renal failure
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DOI：
10.1681/asn.2006101176
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发表时间：
2007-03-01
影响因子：
13.6
通讯作者：
Quigg, Richard J.
中科院分区：
文献类型：
--
作者：
Bao, Lihua;Wang, Ying;Quigg, Richard J.
C3转化酶调节剂Crry的缺乏在小鼠中是胚胎致死的，除非C3也不存在。为了评估在完整补体系统的情况下局部肾Crry缺陷的影响，将Crry（-/-）C3（-/-）小鼠肾移植到同基因C57 BL/6野生型小鼠中。这些Crry缺陷的肾脏出现了明显的炎性细胞浸润、肾小管损伤和间质纤维化，而对照移植肾中不存在类似的变化。血管和肾小管中的强C3沉积与疾病的测量显著相关，这支持补体激活在该模型中是致病性的。微阵列研究表明，上调了一些趋化因子和细胞外基质基因，CCL 2和CXCL 10 mRNA和III型胶原蛋白的验证。通过切除两个自体肾来评估这些病理生理学发现的功能意义，因此移植肾单独提供肾功能。在移植后21天内，与13个对照组中的2个相比，补体充足的野生型宿主中的8个Crry缺陷肾中有7个失败（P = 0.001），最终血尿素氮水平分别为133.9 +/- 33.0和55.6 +/- 8.3 mg/dl（P = 0.015）。这些数据表明，小鼠Crry是肾脏中的关键补体调节剂。当不存在时，发生不受限制的补体激活，并迅速导致显著的炎症和进行性肾衰竭，具有与补体调节存在潜在缺陷的人类疾病相关的特征，如溶血性尿毒症综合征。
Deficiency of the C3 convertase regulator Crry is embryonic lethal in mice unless C3 also is absent. For evaluation of the effect of local kidney Crry deficiency in the setting of an intact complement system, Crry(-/-)C3(-/-) mouse kidneys were transplanted into syngeneic C57BL/6 wild-type mice. These Crry-deficient kidneys developed marked inflammatory cell infiltration, tubular damage, and interstitial fibrosis, whereas similar changes were absent in control transplanted kidneys. Strong C3 deposition in the vessels and tubules that correlated significantly with measures of disease supported that complement activation was pathogenic in this model. Microarray studies showed upregulation of a number of chemokine and extracellular matrix genes, which were validated for CCL2 and CXCL10 mRNA and collagen III protein. The functional significance of these pathophysiologic findings was evaluated by removing both native kidneys, so the transplanted kidney alone provided renal function. Within 21 d of transplantation, seven of eight Crry-deficient kidneys in complement-sufficient wild-type hosts failed, compared with two of 13 controls (P = 0.001), with final blood urea nitrogen levels of 133.9 +/- 33.0 and 55.6 +/- 8.3 mg/dl, respectively (P = 0.015). These data show that mouse Crry is a critical complement regulator in the kidney. When absent, unrestricted complement activation occurs and quickly leads to marked inflammation and progressive renal failure, with features relevant to human diseases with underlying defects in complement regulation, such as hemolytic uremic syndrome.