Pathophysiological significances of ER stress in the kidney : A lesson from novel renal failure model rats

肾脏 ER 应激的病理生理学意义：新型肾衰竭模型大鼠的教训

• 批准号: 17590848
• 负责人: INAGI Reiko
• 金额: $ 2.24万
• 依托单位: Tokai University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590848/
• 关键词: endoplasmic reticulum; podocytes; serpinopathy; misfolding proteins; megsin; proteinuria; transgenic rats; hyperglycemia; トランスジェニックラット

An imbalance between protein load and folding capacity is referred to as endoplasmic reticulum (ER) stress. ER stress is known to be related to progression of some protein conformational diseases such as neuronal disorder and diabetes mellitus. However a role of ER stress in the kidney diseases is still unclear yet. In this study, we evaluate pathophysiological significances of ER stress in the kidney.In transgenic rats overexpressing megsin, a recently discovered renal serine protease inhibitor (serpin), renal lesions characteristic of serpinopathies, caused by the intracellular polymerization of abnormal serpins, were observed. Large amount of megsin was polymerized and formed intracellular inclusions mainly in the ER of glomerular epithelial and distal tubular cells of megsin transgenic rats. These phenomena were associated with proteinuria. The ER stress level was markedly increased in podocytes of megsin transgenic rats, and subsequently developed podocyte injury. In contrast, rats overexpressing a mutant megsin, characterized by a deficient conformational transition activity, did not develop the serpinopathy associated with renal dysfunction, proteinuria, and ER stress.In experimental nephrosis rats, we demonstrated that ER stress was induced in the tubular cells exposed to proteinuria followed by apoptosis. Our in vitro study utilizing cultured rat tubular cells also showed that exposure to high concentration of albumin induced ER stress associated with apoptosis in these cells.These results suggest for the first time pathophysiological significances of ER stress in renal diseases.

蛋白质负载和折叠能力之间的不平衡被称为内质网（ER）应激。内质网应激与一些蛋白质构象疾病如神经元疾病和糖尿病的进展有关。然而，ER应激在肾脏疾病中的作用仍不清楚。在这项研究中，我们评估ER应激在肾脏中的病理生理学意义。在过度表达megsin的转基因大鼠中，观察到一种最近发现的肾脏丝氨酸蛋白酶抑制剂（serpin），由异常serpins的细胞内聚合引起的serpinopathies特征性肾脏病变。megsin转基因大鼠肾小球上皮细胞和远端肾小管上皮细胞的内质网中有大量的megsin聚合形成包涵体。这些现象与蛋白尿有关。雌激素受体应激水平明显增加，足细胞损伤。相比之下，大鼠过度表达的突变megsin，其特征在于由一个缺陷的构象转换活动，没有开发与肾功能不全，蛋白尿，和ER stress.In实验性肾病大鼠的丝氨酸蛋白酶抑制剂病，我们证明，ER应激诱导肾小管细胞暴露于蛋白尿，然后凋亡。我们在体外培养的大鼠肾小管细胞的研究也表明，暴露于高浓度的白蛋白诱导ER应激与这些细胞的凋亡。这些结果首次提出了ER应激在肾脏疾病的病理生理意义。

项目成果

Protection of endothelial cells by dextran sulfate in rats With thrombotic microangiopathy.

硫酸葡聚糖对血栓性微血管病大鼠内皮细胞的保护作用。

• 发表时间: 2005
• 期刊: J Am Soc Nephrol 16
• 作者: Eto N;et al.
• 通讯作者: et al.

Hypoxia-inducible factor modulates tubular cell survival in cisplatin nephrotoxicity

• DOI: 10.1152/ajprenal.00081.2005
• 发表时间: 2005-11-01
• 期刊: AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
• 影响因子: 4.2
• 作者: Tanaka, T;Kojima, I;Nangaku, M
• 通讯作者: Nangaku, M

A rat model of human FENIB (familial encephalopathy with neuroserpin inclusion bodies).

• DOI: 10.1016/j.bbrc.2006.06.016
• 发表时间: 2006-08
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: K. Takano;Y. Kitao;R. Inagi;T. Momoi;T. Matsuyama;T. Miyata;Y. Yoneda;H. Iso;D. Stern;O. Hori;S. Ogawa

Pyridoxamine improves functional, structural, and biochemical alterations of peritoneal membranes in uremic peritoneal dialysis rats

• DOI: 10.1111/j.1523-1755.2005.00531.x
• 发表时间: 2005-09-01
• 期刊: KIDNEY INTERNATIONAL
• 影响因子: 19.6
• 作者: Kakuta, T;Tanaka, R;Miyata, T
• 通讯作者: Miyata, T

Involvement of endoplasmic reticulum (ER) stress in podocyte injury induced by excessive protein accumulation

• DOI: 10.1111/j.1523-1755.2005.00736.x
• 发表时间: 2005-12-01
• 期刊: KIDNEY INTERNATIONAL
• 影响因子: 19.6
• 作者: Inagi, R;Nangaku, M;Miyata, T
• 通讯作者: Miyata, T