Fujii Y, Khoshnoodi J, Takenaka H, Hosoyamada M, Nakajo A, Bessho F, Kudo A, Takahashi S, Arimura Y, Yamada A, Nagasawa T, Ruotsalainen V, Tryggvason K, Lee A S, Yan K
Department of Internal Medicine, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.
Kidney Int. 2006 Apr;69(8):1350-9. doi: 10.1038/sj.ki.5000317.
The mechanism by which glucocorticoids govern antiproteinuric effect in nephrotic syndrome remains unknown. Present study examined the protective role of dexamethasone (DEX) in the intracellular trafficking of nephrin under endoplasmic reticulum (ER) stress. Human embryonic kidney-293 cell line expressing a full-length human nephrin was cultured in mediums containing 5.5 or 25 mM glucose with or without DEX. The result revealed that glucose starvation evoked a rapid ER stress leading to formation of underglycosylated nephrin that was remained in the ER as a complex with calreticulin/calnexin. DEX rescued this interfered trafficking through binding to its receptor and stimulating the mitochondrial transcripts and adenosine 5' triphosphate (ATP) production, leading to synthesis of fully glycosylated nephrin. These results suggest that ER-stress in podocytes may cause alteration of nephrin N-glycosylation, which may be an underlying factor in the pathomechanism of the proteinuria in nephrotic syndrome. DEX may restore this imbalance by stimulating expression of mitochondrial genes, resulted in the production of ATP that is essential factor for proper folding machinery aided by the ER chaperones.
糖皮质激素在肾病综合征中发挥抗蛋白尿作用的机制尚不清楚。本研究探讨了地塞米松（DEX）在内质网（ER）应激下对nephrin细胞内转运的保护作用。将表达全长人nephrin的人胚肾-293细胞系培养在含有5.5或25 mM葡萄糖且添加或不添加DEX的培养基中。结果显示，葡萄糖饥饿引发快速的内质网应激，导致形成低糖基化的nephrin，其作为与钙网蛋白/钙连蛋白的复合物保留在内质网中。DEX通过与其受体结合并刺激线粒体转录本和5'-三磷酸腺苷（ATP）的产生来挽救这种受干扰的转运，从而导致完全糖基化的nephrin的合成。这些结果表明，足细胞中的内质网应激可能导致nephrin N-糖基化改变，这可能是肾病综合征蛋白尿发病机制中的一个潜在因素。DEX可能通过刺激线粒体基因的表达来恢复这种失衡，从而产生ATP，这是在内质网伴侣辅助下正确折叠机制所必需的因素。
