HANAC Syndrome Col4a1 Mutation Causes Neonate Glomerular Hyperpermeability and Adult Glomerulocystic Kidney Disease
HANAC Syndrome Col4a1 Mutation Causes Neonate Glomerular Hyperpermeability and Adult Glomerulocystic Kidney Disease
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DOI：
10.1681/asn.2014121217
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发表时间：
2016-04-01
影响因子：
13.6
通讯作者：
Plaisier, Emmanuelle
中科院分区：
文献类型：
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作者：
Chen, Zhiyong;Migeon, Tiffany;Plaisier, Emmanuelle
遗传性血管病变、肾病、动脉瘤和肌肉痉挛(Hanac)综合征是一种常染色体显性遗传综合征，由编码IV型胶原蛋白α1链的COL4A1突变引起，IV型胶原蛋白是基底膜的主要成分。患者出现脑部小血管疾病、视网膜扭曲、肌肉痉挛和肾脏疾病，包括多发性肾囊肿、慢性肾功能衰竭，有时还会出现血尿。产生Hanac综合征的突变定位于包含COL4A1蛋白的CB3[IV]片段的整合素结合部位。为了研究Hanac综合征的病理生理学，我们培育了携带Col4a1 p.Gly498Val突变的小鼠，该突变在一个HANAC综合征家族中被发现。Col4a1 G498V突变可导致肾小球发育延迟，足细胞分化延迟，但肾单位数目不减少，导致新生儿白质尿和血尿。肾小球缺陷在第一个月内消失，但3个月大的突变小鼠出现肾小球囊肿。包膜结构异常与金属蛋白酶诱导和激活异常表达CD44、α-SMA、ILK和DDR1的肾小球壁上皮细胞有关。肾小球和小动脉周围可见炎性细胞浸润。纯合子Col4a1 G498V突变小鼠还表现出乳头畸形和尿液浓度缺陷。这些结果揭示了胚胎肾小球基底膜中的α1α1α2胶原IV型分子的发育作用，影响足细胞的分化。COL4A1相关疾病患者肾小球囊内胶原网络的分子改变与壁上皮细胞激活、基质重塑和炎症之间的关系可能是肾小球囊变和慢性肾脏病的原因之一。
Hereditary angiopathy, nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is an autosomal dominant syndrome caused by mutations in COL4A1 that encodes the alpha 1 chain of collagen IV, a major component of basement membranes. Patients present with cerebral small vessel disease, retinal tortuosity, muscle cramps, and kidney disease consisting of multiple renal cysts, chronic kidney failure, and sometimes hematuria. Mutations producing HANAC syndrome localize within the integrin binding site containing CB3[IV] fragment of the COL4A1 protein. To investigate the pathophysiology of HANAC syndrome, we generated mice harboring the Col4a1 p.Gly498Val mutation identified in a family with the syndrome. Col4a1 G498V mutation resulted in delayed glomerulogenesis and podocyte differentiation without reduction of nephron number, causing albunninuria and hematuria in newborns. The glomerular defects resolved within the first month, but glomerular cysts developed in 3-month-old mutant mice. Abnormal structure of Bowman's capsule was associated with metalloproteinase induction and activation of the glomerular parietal epithelial cells that abnormally expressed CD44, alpha-SMA, ILK, and DDR1. Inflammatory infiltrates were observed around glomeruli and arterioles. Homozygous Col4a1 G498V mutant mice additionally showed dysmorphic papillae and urinary concentration defects. These results reveal a developmental role for the alpha 1 alpha 1 alpha 2 collagen IV molecule in the embryonic glomerular basement membrane, affecting podocyte differentiation. The observed association between molecular alteration of the collagenous network in Bowman's capsule of the mature kidney and activation of parietal epithelial cells, matrix remodeling, and inflammation may account for glomerular cyst development and CKD in patients with COL4A1-related disorders.