Mizoribine corrects defective nephrin biogenesis by restoring intracellular energy balance
Mizoribine corrects defective nephrin biogenesis by restoring intracellular energy balance
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DOI：
10.1681/asn.2006070732
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发表时间：
2007-09-01
影响因子：
13.6
通讯作者：
Yan, Kunimasa
中科院分区：
文献类型：
--
作者：
Nakajo, Aya;Khoshnoodi, Jamshid;Yan, Kunimasa
蛋白质在内质网（ER）内被修饰和折叠。当蛋白质的流入超过内质网处理负荷的能力时，内质网就会受到“压力”，蛋白质的生物生成就会受到影响。我们之前已经证明足细胞中ATP耗竭诱导内质网应激会导致肾素定位错误和随后的足细胞损伤。本研究的目的是确定内质网应激是否与体内蛋白尿有关，以及免疫抑制剂米佐利滨是否可以通过恢复正常的肾素生物生成来发挥其抗蛋白尿作用。嘌呤霉素氨基核苷诱导小鼠肾范围蛋白尿增加足细胞内质网应激标志物GRP78的表达，导致肾素错定位到细胞质。在体外实验中，米佐瑞滨通过一种可能依赖于足细胞中肌苷5'-单磷酸脱氢酶（IMPDH）活性抑制的机制，通过增加ATP水平恢复细胞内能量平衡，并纠正肾素的翻译后加工。因此，我们推测米佐利滨可能通过恢复受伤足细胞中狭缝隔膜蛋白的生物发生，至少在一定程度上诱导蛋白尿缓解。对内质网微环境的进一步了解可能会导致新的方法来治疗蛋白质异常处理在发病机制中起作用的疾病。
Proteins are modified and folded within the endoplasmic reticulum (ER). When the influx of proteins exceeds the capacity of the ER to handle the load, the ER is "stressed" and protein biogenesis is affected. We have previously shown that the induction of ER stress by ATP depletion in podocytes leads to mislocalization of nephrin and subsequent injury of podocytes. The aim of the present study was to determine whether ER stress is associated with proteinuria in vivo and whether the immunosuppressant mizoribine may exert its antiproteinuric effect by restoring normal nephrin biogenesis. Induction of nephrotic-range proteinuria with puromycin aminonucleoside in mice increased expression of the ER stress marker GRP78 in podocytes, and led to the mislocalization of nephrin to the cytoplasm. In vitro, mizoribine, through a mechanism likely dependent on the inhibition of inosine 5'-monophosphate dehydrogenase (IMPDH) activity in podocytes, restored the intracellular energy balance by increasing levels of ATP and corrected the posttranslational processing of nephrin. Therefore, we speculate that mizoribine may induce remission of proteinuria, at least in part, by restoring the biogenesis of slit diaphragm proteins in injured podocytes. Further understanding of the ER microenvironment may lead to novel approaches to treat diseases in which abnormal handling of proteins plays a role in pathogenesis.