Lupus Nephritis IgG Induction of Calcium/Calmodulin-Dependent Protein Kinase IV Expression in Podocytes and Alteration of Their Function.
Lupus Nephritis IgG Induction of Calcium/Calmodulin-Dependent Protein Kinase IV Expression in Podocytes and Alteration of Their Function.
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DOI：
10.1002/art.39499
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发表时间：
2016-04
期刊：
影响因子：
--
通讯作者：
Tsokos GC
中科院分区：
文献类型：
--
作者：
Ichinose K;Ushigusa T;Nishino A;Nakashima Y;Suzuki T;Horai Y;Koga T;Kawashiri SY;Iwamoto N;Tamai M;Arima K;Nakamura H;Obata Y;Yamamoto K;Origuchi T;Nishino T;Kawakami A;Tsokos GC
肾足细胞及其裂隙横隔膜可防止尿蛋白丢失。系统性红斑狼疮患者T细胞钙/钙调素依赖性蛋白激酶IV(CaMKIV)表达增加。本研究旨在探讨CaMKIV在狼疮性肾炎(LN)足细胞功能中的作用。我们用来自健康人或LN患者的免疫球蛋白处理肾足细胞，然后用DNA微阵列分析基因表达。免疫荧光染色分析在有或无Fc受体(FcRN)沉默的情况下足细胞内免疫球蛋白的定位。此外，我们还沉默了足细胞中的CAMK4，并分析了所选基因的表达。我们还用原位杂交法检测了mrl/lpr、mrl/lpr.camkiv−/−和mrl/mpj小鼠肾脏足细胞中CD86的表达。我们发现足细胞暴露于免疫球蛋白会导致免疫球蛋白进入细胞质。免疫球蛋白通过FcRN进入足细胞，这是因为经FcRN小干扰RNA处理的足细胞胞浆中的免疫球蛋白较少。对暴露于LN来源的免疫球蛋白的足细胞的DNA微阵列研究显示，与免疫细胞激活或足细胞损伤相关的基因上调。有趣的是，在足细胞中沉默CAMK4后，CD86的表达减少。原位杂交实验显示mrl/lpr.camkiv−/−小鼠足细胞中CD86mRNA的表达降低。LN来源的免疫球蛋白进入足细胞并上调CAMK4，随后是已知与足细胞损伤和T细胞激活有关的基因表达增加。靶向抑制足细胞中的CAMK4在LN患者中可能被证明是临床有用的。
Kidney podocytes and their slit diaphragms prevent urinary protein loss. T cells from patients with systemic lupus erythematosus display increased expression of calcium/calmodulin-dependent protein kinase IV (CaMKIV). The present study was undertaken to investigate the role of CaMKIV in podocyte function in lupus nephritis (LN). We treated kidney podocytes with IgG derived from healthy individuals or patients with LN and then analyzed gene expression using a DNA microarray. The localization of IgG in podocytes was analyzed by immunofluorescence staining, with or without silencing of neonatal Fc receptor (FcRn). In addition, we silenced CAMK4 in podocytes and analyzed the expression of selected genes. We also examined the expression of CD86 in kidney podocytes from MRL/lpr, MRL/lpr.camkiv−/−, and MRL/MPJ mice by in situ hybridization. We found that exposure of podocytes to IgG resulted in entry of IgG into the cytoplasm. IgG entered podocytes via the FcRn because less IgG was found in the cytoplasm of podocytes treated with FcRn small interfering RNA. DNA microarray studies of podocytes exposed to LN-derived IgG revealed up-regulation of genes related to the activation of immune cells or podocyte damage. Interestingly, CD86 expression decreased after silencing CAMK4 in podocytes. Also, in situ hybridization experiments showed that the expression of CD86 was reduced in podocytes from MRL/lpr.camkiv−/− mice. LN-derived IgG enters podocytes and up-regulates CAMK4, which is followed by increased expression of genes known to be linked to podocyte damage and T cell activation. Targeted inhibition of CAMK4 in podocytes may prove to be clinically useful in patients with LN.
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影响因子：
4.4
作者：
Ichinose, Kunihiro;Rauen, Thomas;Tsokos, George C.
通讯作者：
Tsokos, George C.
影响因子：
18.2
作者：
Greka A;Mundel P
通讯作者：
Mundel P
DOI：
10.4049/jimmunol.1201785
发表时间：
2012-10-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Koga T;Ichinose K;Mizui M;Crispín JC;Tsokos GC
通讯作者：
Tsokos GC
影响因子：
14.9
作者：
Barrett T;Troup DB;Wilhite SE;Ledoux P;Evangelista C;Kim IF;Tomashevsky M;Marshall KA;Phillippy KH;Sherman PM;Muertter RN;Holko M;Ayanbule O;Yefanov A;Soboleva A
通讯作者：
Soboleva A
影响因子：
7.7
作者：
Ichinose, K;Maeshima, Y;Makino, H
通讯作者：
Makino, H