SIRPα signaling regulates podocyte structure and function
SIRPα signaling regulates podocyte structure and function
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SIRPα 信号调节足细胞结构和功能
DOI：
10.1152/ajprenal.00597.2012
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Nojima Y
中科院分区：
文献类型：
--
作者：
Takahashi S;Tomioka M;Hiromura K;Sakairi T;Hamatani H;Watanabe M;Ikeuchi H;Kaneko Y;Maeshima A;Aoki T;Ohnishi H;Matozaki T;Nojima Y
信号调节蛋白-α (SIRPα)是一种跨膜蛋白，其细胞质区含有酪氨酸磷酸化位点；两种酪氨酸磷酸酶，SHP-1和SHP-2，以磷酸化依赖的方式结合到这些位点并转导多种细胞内信号。近年来，研究人员发现SIRPα是肾小球中主要的酪氨酸磷酸化蛋白之一，并在足细胞中表达。在本研究中，我们使用敲入小鼠（C57BL/6背景）表达缺乏细胞质区域的SIRPα突变体（SIRPα突变体小鼠）来检测SIRPα表达在足细胞中的作用。光镜检查显示，sirp α-突变小鼠肾脏未见明显形态学异常。另一方面，电镜检查显示，与野生型小鼠相比，sirp α-突变小鼠的足细胞异常，主要突不规则，足突变宽，变平。sirp α-突变小鼠的肾功能明显受损，出现轻微蛋白尿。此外，阿霉素注射在sirp α-突变小鼠中诱导大量蛋白尿并局灶性肾小球硬化，而其野生型小鼠对阿霉素诱导的肾病具有抗性。这些数据表明，在生理和病理条件下，SIRPα作为一种过滤屏障参与足细胞结构的调节和功能。
Signal-regulatory protein-α (SIRPα) is a transmembrane protein that contains tyrosine phosphorylation sites in its cytoplasmic region; two tyrosine phosphatases, SHP-1 and SHP-2, bind to these sites in a phosphorylation-dependent manner and transduce multiple intracellular signals. Recently, SIRPα was identified as one of the major tyrosine-phosphorylated proteins in the glomeruli and found to be expressed in podocytes. In the present study, we examined the role of SIRPα expression in podocytes using knockin mice (C57BL/6 background) expressing mutant SIRPα that lacks a cytoplasmic region (SIRPα-mutant mice). Light microscopic examination revealed no apparent morphological abnormalities in the kidneys of the SIRPα-mutant mice. On the other hand, electron microscopic examination revealed abnormal podocytes with irregular major processes and wider and flattened foot processes in the SIRPα-mutant mice compared with their wild-type counterparts. Significantly impaired renal functions and slight albuminuria were demonstrated in the SIRPα-mutant mice. In addition, adriamycin injection induced massive albuminuria together with focal glomerulosclerosis in the SIRPα-mutant mice, while their wild-type counterparts were resistant to adriamycin-induced nephropathy. These data demonstrate that SIRPα is involved in the regulation of podocyte structure and function as a filtration barrier under both physiological and pathological conditions.