KANK deficiency leads to pod ocyte dysfunction and nephrotic syndrome
KANK deficiency leads to pod ocyte dysfunction and nephrotic syndrome
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DOI：
10.1172/jci79504
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发表时间：
2015-06-01
影响因子：
15.9
通讯作者：
Hildebrandt, Friedhelm
中科院分区：
文献类型：
--
作者：
Gee, Heon Yung;Zhang, Fujian;Hildebrandt, Friedhelm
类固醇耐药肾病综合征（SRNS）是一种常见的原因进行性肾功能下降，并影响数百万人。在最近的一项研究中，30%的SRNS病例是27个不同基因中的1个单基因突变的结果。在这里，使用纯合性作图和全外显子组测序，我们确定了肾病综合征患者肾锚蛋白重复序列蛋白1（KANK1），KANK2和KANK4的隐性突变。在一个独立的功能遗传筛选果蝇心脏肾细胞，这是相当于哺乳动物足细胞，我们确定，果蝇KANK同源物（dKank）是必不可少的肾细胞功能。肾细胞中RNAi介导的dKank敲低破坏了狭缝隔膜过滤结构和腔隙通道结构。在大鼠中，KANK1、KANK2和KANK4均定位于肾小球足细胞，并且KANK1与突触足蛋白部分共定位。在斑马鱼中敲除kank2重演了肾病综合征的表型，导致蛋白尿和足细胞足突消失。在大鼠肾小球和培养的人足细胞中，KANK2与ARHGDIA相互作用，ARHGDIA是一种已知的足细胞中RHO GTP酶的调节剂，在某些类型的肾病综合征中功能失调。在培养的足细胞中敲低KANK2增加了活性GTP结合的RHOA并减少了迁移。总之，这些数据表明，KANK家族基因在足细胞功能中发挥进化保守的作用，可能是通过调节RHO GT3信号传导。
Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of progressive renal function decline and affects millions of people. In a recent study, 30% of SRNS cases evaluated were the result of monogenic mutations in 1 of 27 different genes. Here, using homozygosity mapping and whole-exome sequencing, we identified recessive mutations in kidney ankyrin repeat-containing protein 1 (KANK1), KANK2, and KANK4 in individuals with nephrotic syndrome. In an independent functional genetic screen of Drosophila cardiac nephrocytes, which are equivalents of mammalian podocytes, we determined that the Drosophila KANK homolog (dKank) is essential for nephrocyte function. RNAi-mediated knockdown of dKank in nephrocytes disrupted slit diaphragm filtration structures and lacuna channel structures. In rats, KANK1, KANK2, and KANK4 all localized to podocytes in glomeruli, and KANK1 partially colocalizeci with synaptopodin. Knockdown of kank2 in zebrafish recapitulated a nephrotic syndrome phenotype, resulting in proteinuria and podocyte foot process effacement. In rat glomeruli and cultured human podocytes, KANK2 interacted with ARHGDIA, a known regulator of RHO GTPases in podocytes that is dysfunctional in some types of nephrotic syndrome. Knockdown of KANK2 in cultured podocytes increased active GTP-bound RHOA and decreased migration. Together, these data suggest that KANK family genes play evolutionarily conserved roles in podocyte function, likely through regulating RHO GTPase signaling.