Albumin-induced podocyte injury and protection are associated with regulation of COX-2.
Albumin-induced podocyte injury and protection are associated with regulation of COX-2.
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DOI：
10.1038/ki.2014.196
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发表时间：
2014-12
影响因子：
19.6
通讯作者：
中科院分区：
文献类型：
--
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白蛋白尿是进行性肾小球疾病的标志和危险因素，并导致足细胞暴露于血清白蛋白及其相关因子的增加。在此，使用体内和体外血清白蛋白超负荷模型来检验白蛋白诱导的蛋白尿和足细胞损伤与考克斯-2诱导直接相关的假设。白蛋白诱导大鼠肾小球和足细胞中的考克斯-2、MCP-1、CXCL 1和应激蛋白HSP 25，同时还诱导足细胞中的B7-1和HSP 70 i。足细胞暴露于白蛋白会诱导mRNA和蛋白质的表达，并增强考克斯-2（肾脏血流动力学和炎症的关键调节因子）mRNA的稳定性，从而使足细胞容易受到损伤。足细胞暴露于白蛋白也刺激了几种激酶（p38 MAPK、MK2、JNK/SAPK和ERK 1/2），其抑制剂（JNK/SAPK除外）下调白蛋白诱导的考克斯-2。AMPK、PKC和NFκB的抑制也下调了白蛋白诱导的考克斯-2。重要的是，白蛋白诱导的考克斯-2也被糖皮质激素和噻唑烷二酮类抑制，这两种药物都直接保护足细胞免受损伤。此外，特定的白蛋白相关脂肪酸被鉴定为考克斯-2诱导、足细胞损伤和蛋白尿的重要贡献者。因此，考克斯-2与蛋白尿期间足细胞损伤有关，也与糖皮质激素和噻唑烷二酮类给予的足细胞保护有关。此外，考克斯-2诱导，足细胞损伤和白蛋白尿似乎主要由血清白蛋白相关脂肪酸介导。
Albuminuria is both a hallmark and a risk factor for progressive glomerular disease, and results in increased exposure of podocytes to serum albumin with its associated factors. Here in vivo and in vitro models of serum albumin overload were used to test the hypothesis that albumin-induced proteinuria and podocyte injury directly correlate with COX-2 induction. Albumin induced COX-2, MCP-1, CXCL1 and the stress protein HSP25 in both rat glomeruli and cultured podocytes, while B7-1 and HSP70i were also induced in podocytes. Podocyte exposure to albumin induced both mRNA and protein and enhanced the mRNA stability of COX-2, a key regulator of renal hemodynamics and inflammation, which renders podocytes susceptible to injury. Podocyte exposure to albumin also stimulated several kinases (p38 MAPK, MK2, JNK/SAPK and ERK1/2), inhibitors of which (except JNK/SAPK) down-regulated albumin-induced COX-2. Inhibition of AMPK, PKC and NFκB also down-regulated albumin-induced COX-2. Critically, albumin-induced COX-2 was also inhibited by glucocorticoids and thiazolidinediones, both of which directly protect podocytes against injury. Furthermore, specific albumin-associated fatty acids were identified as important contributors to COX-2 induction, podocyte injury and proteinuria. Thus, COX-2 is associated with podocyte injury during albuminuria, as well as with the known podocyte protection imparted by glucocorticoids and thiazolidinediones. Moreover, COX-2 induction, podocyte damage and albuminuria appear mediated largely by serum albumin-associated fatty acids.
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作者：
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