Apelin promotes diabetic nephropathy by inducing podocyte dysfunction via inhibiting proteasome activities.
Apelin promotes diabetic nephropathy by inducing podocyte dysfunction via inhibiting proteasome activities.
复制标题
Apelin 通过抑制蛋白酶体活性诱导足细胞功能障碍而促进糖尿病肾病
DOI：
10.1111/jcmm.12619
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发表时间：
2015-09
影响因子：
5.3
通讯作者：
Zeng X
中科院分区：
文献类型：
--
作者：
Guo C;Liu Y;Zhao W;Wei S;Zhang X;Wang W;Zeng X
足细胞损伤与糖尿病肾病（DN）的进展相关。Apelin是一种脂肪细胞衍生肽，已被报道是DN的促进因子。在这项研究中，我们的目的是确定爱帕琳是否通过诱导足细胞功能障碍促进DN的进展。kk-Ay小鼠作为DN模型。分别腹腔注射Apelin及其拮抗剂F13 A 4周。分析肾功能和足突蛋白以评估爱帕琳对kk-Ay小鼠和足细胞的影响。Apelin增加kk-Ay小鼠的蛋白尿和足细胞足突蛋白表达，这与DN患者或小鼠肾小球中Apelin受体（APLNR）水平增加的结果一致。在培养的足细胞中，高葡萄糖增加APLNR的表达和apelin管理与增加的渗透性和降低足突蛋白水平。所有这些功能障碍都与kk-Ay小鼠和培养足细胞中26 S蛋白酶体活性降低和多聚泛素化蛋白增加有关，如环磷酸腺苷（cAMP）或橄榄苦苷激活26 S蛋白酶体所示。这些作用似乎与内质网（ER）应激有关，因为在高糖和apelin处理的足细胞中，apelin增加C/EBP同源蛋白（CHOP）和peiFα水平，而cAMP或橄榄苦苷降低其水平。这些结果表明，爱帕琳诱导足细胞功能障碍，通过内质网应激，这是由蛋白酶体活性降低诱导的DN。
Podocyte injuries are associated with progression of diabetic nephropathy (DN). Apelin, an adipocyte-derived peptide, has been reported to be a promoting factor for DN. In this study, we aim to determine whether apelin promotes progression of DN by inducing podocyte dysfunction. kk-Ay mice were used as models for DN. Apelin and its antagonist, F13A were intraperitoneally administered for 4 weeks, respectively. Renal function and foot process proteins were analysed to evaluate the effects of apelin on kk-Ay mice and podocytes. Apelin increased albuminuria and decreased podocyte foot process proteins expression in kk-Ay mice, which is consistent with the results that apelin receptor (APLNR) levels increased in glomeruli of patients or mice with DN. In cultured podocytes, high glucose increased APLNR expression and apelin administration was associated with increased permeability and decreased foot process proteins levels. All these dysfunctions were associated with decreased 26S proteasome activities and increased polyubiquitinated proteins in both kk-Ay mice and cultured podocytes, as demonstrated by 26S proteasome activation with cyclic adenosine monophosphate (cAMP) or oleuropein. These effects seemed to be related to endoplasmic reticulum (ER) stress, as apelin increased C/EBP homologous protein (CHOP) and peiFα levels while cAMP or oleuropein reduced it in high glucose and apelin treated podocytes. These results suggest that apelin induces podocyte dysfunction in DN through ER stress which was induced by decreased proteasome activities in podocytes.