Lack of Cathepsin D in the Renal Proximal Tubular Cells Resulted in Increased Sensitivity against Renal Ischemia/Reperfusion Injury
Lack of Cathepsin D in the Renal Proximal Tubular Cells Resulted in Increased Sensitivity against Renal Ischemia/Reperfusion Injury
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DOI：
10.3390/ijms20071711
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发表时间：
2019-04-05
影响因子：
5.6
通讯作者：
Uchiyama, Yasuo
中科院分区：
文献类型：
--
作者：
Suzuki, Chigure;Tanida, Isei;Uchiyama, Yasuo
组织蛋白酶D是主要的溶酶体天冬氨酸蛋白酶之一，其对于自噬-溶酶体系统的正常功能是必需的。在肾脏中，组织蛋白酶D在肾近端小管上皮细胞中富集，并且其水平在急性肾损伤期间增加。为了研究组织蛋白酶D缺乏如何影响肾近端小管细胞，我们采用了条件性敲除CtsD（flox/-）; Spink 3（Cre）小鼠。使用抗组织蛋白酶D抗体的免疫组织化学分析显示，组织蛋白酶D显着减少，在肾小管上皮细胞的皮质-髓质区，主要是在肾近端小管细胞的这只小鼠。组织蛋白酶D缺陷的肾近端小管细胞显示微管相关蛋白轻链3（LC 3;自噬体/自溶酶体的标志物）信号的增加和异常自噬结构的积累。肾缺血/再灌注损伤导致CtsD（flox/-）; Spink 3（Cre）小鼠的组织蛋白酶D缺陷型肾小管上皮细胞中早期肾损伤标志物肾损伤分子1（Kim-1）增加。CtsD（flox/-）; Spink 3（Cre）小鼠的皮质-髓质区的炎症标志物也增加。我们的结果表明，缺乏组织蛋白酶D的肾小管上皮细胞对缺血/再灌注损伤的敏感性增加。
Cathepsin D is one of the major lysosomal aspartic proteases that is essential for the normal functioning of the autophagy-lysosomal system. In the kidney, cathepsin D is enriched in renal proximal tubular epithelial cells, and its levels increase during acute kidney injury. To investigate how cathepsin D-deficiency impacts renal proximal tubular cells, we employed a conditional knockout CtsD(flox/-); Spink3(Cre) mouse. Immunohistochemical analyses using anti-cathepsin D antibody revealed that cathepsin D was significantly decreased in tubular epithelial cells of the cortico-medullary region, mainly in renal proximal tubular cells of this mouse. Cathepsin D-deficient renal proximal tubular cells showed an increase of microtubule-associated protein light chain 3 (LC3; a marker for autophagosome/autolysosome)-signals and an accumulation of abnormal autophagic structures. Renal ischemia/reperfusion injury resulted in an increase of early kidney injury marker, Kidney injury molecule 1 (Kim-1), in the cathepsin D-deficient renal tubular epithelial cells of the CtsD(flox/-); Spink3(Cre) mouse. Inflammation marker was also increased in the cortico-medullary region of the CtsD(flox/-); Spink3(Cre) mouse. Our results indicated that lack of cathepsin D in the renal tubular epithelial cells led to an increase of sensitivity against ischemia/reperfusion injury.