Cathepsin D in Podocytes Is Important in the Pathogenesis of Proteinuria and CKD.
Cathepsin D in Podocytes Is Important in the Pathogenesis of Proteinuria and CKD.
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DOI：
10.1681/asn.2015040366
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发表时间：
2016-01
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影响因子：
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通讯作者：
Kanae Yamamoto-Nonaka;M. Koike;K. Asanuma;M. Takagi;Juan Alejandro Oliva Trejo;Takuto Seki;Teruo Hidaka-Teruo
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文献类型：
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作者：
Kanae Yamamoto-Nonaka;M. Koike;K. Asanuma;M. Takagi;Juan Alejandro Oliva Trejo;Takuto Seki;Teruo Hidaka-Teruo
研究发现足细胞和神经元之间有许多相似之处，这些相似之处可能是阐明足细胞损伤发病机制的关键。组织蛋白酶D（CD）是溶酶体中具有代表性的天冬氨酸蛋白酶。CD缺陷小鼠的中枢神经系统神经元表现出一种溶酶体贮积病，其表型类似于神经元蜡样脂褐质沉积症。在肾脏中，CD在足细胞中的作用尚未完全探索。在此，我们产生了足细胞特异性CD敲除小鼠，其在5个月大时发生蛋白尿，在20-22个月大时发生ESRD。这些小鼠的免疫组织化学分析显示，随着年龄的增长，足细胞凋亡死亡，随后出现蛋白尿和肾小球硬化。使用电子显微镜，我们确定，在足细胞，颗粒嗜锇沉积物（GROD），自噬体/自溶小体样机构，和指纹图谱，CD缺陷神经元的典型标志。足细胞中的CD缺乏也导致了自噬损伤和线粒体ATP合酶亚基c在GROD中的积累的指示性蛋白质的自溶酶体降解和积累的停止，再次类似于CD缺乏神经元中报道的变化。此外，podocin和nephrin，狭缝隔膜的两个基本组成部分，易位Rab 7和溶酶体相关的膜糖蛋白1阳性两性体/autolysosomes，在足细胞特异性CD敲除小鼠的足细胞细胞体中积累。我们推测，缺陷的溶酶体活性导致足突消失引起足蛋白和nephrin的这种积累。总体而言，我们的研究结果表明，足细胞中CD的丢失导致自噬损伤，触发毒性亚基c阳性脂褐素以及裂膜蛋白的积累，随后发生凋亡性细胞死亡。
Studies have revealed many analogies between podocytes and neurons, and these analogies may be key to elucidating the pathogenesis of podocyte injury. Cathepsin D (CD) is a representative aspartic proteinase in lysosomes. Central nervous system neurons in CD-deficient mice exhibit a form of lysosomal storage disease with a phenotype resembling neuronal ceroid lipofuscinoses. In the kidney, the role of CD in podocytes has not been fully explored. Herein, we generated podocyte-specific CD-knockout mice that developed proteinuria at 5 months of age and ESRD by 20-22 months of age. Immunohistochemical analysis of these mice showed apoptotic podocyte death followed by proteinuria and glomerulosclerosis with aging. Using electron microscopy, we identified, in podocytes, granular osmiophilic deposits (GRODs), autophagosome/autolysosome-like bodies, and fingerprint profiles, typical hallmarks of CD-deficient neurons. CD deficiency in podocytes also led to the cessation of autolysosomal degradation and accumulation of proteins indicative of autophagy impairment and the mitochondrial ATP synthase subunit c accumulation in the GRODs, again similar to changes reported in CD-deficient neurons. Furthermore, both podocin and nephrin, two essential components of the slit diaphragm, translocated to Rab7- and lysosome-associated membrane glycoprotein 1-positive amphisomes/autolysosomes that accumulated in podocyte cell bodies in podocyte-specific CD-knockout mice. We hypothesize that defective lysosomal activity resulting in foot process effacement caused this accumulation of podocin and nephrin. Overall, our results suggest that loss of CD in podocytes causes autophagy impairment, triggering the accumulation of toxic subunit c-positive lipofuscins as well as slit diaphragm proteins followed by apoptotic cell death.