N-glycosylated IgG in patients with kidney transplants increases calcium/calmodulin kinase IV in podocytes and causes injury.
N-glycosylated IgG in patients with kidney transplants increases calcium/calmodulin kinase IV in podocytes and causes injury.
复制标题
DOI：
10.1111/ajt.16140
复制
发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Tsokos GC
中科院分区：
文献类型：
--
作者：
Bhargava R;Maeda K;Tsokos MG;Pavlakis M;Stillman IE;Tsokos GC
移植肾小球病（TG）是晚期同种异体移植物丢失的主要原因。TG中尿podocin/肌酐比值增加表明足细胞损失加速。导致TG足细胞损伤的机制尚不清楚。我们报告说，IgG从肾移植受者与TG，但不是从那些没有TG，导致减少nephrin的表达，显着的足细胞肌动蛋白细胞骨架，和运动的变化。这些变化之前是钙/钙调蛋白激酶IV（CAMK 4）的表达增加。从机制上讲，我们发现CAMK 4磷酸化GSK 3 β（糖原合成酶激酶3 β），激活Wnt途径并稳定nephrin转录抑制因子SNAIL。沉默新生儿Fc受体（FcRn）或CAMK 4可预防TG患者IgG的足细胞损伤作用。此外，我们表明，从这些IgG中去除N-连接的糖基残基并不干扰其进入足细胞，但消除了其上调CAMK 4的能力，并导致足细胞损伤。这些发现的转化价值是由以下事实表明的：CAMK 4在TG患者的足细胞中增加，而在没有TG的患者中没有增加，尽管存在其他形式的肾功能不全。我们的研究结果为限制肾移植患者足细胞损伤提供了新的考虑，足细胞损伤可能导致最终的肾小球不稳定和移植肾小球病。
Transplant glomerulopathy (TG) is a major cause of late allograft loss. Increased urine podocin/creatinine ratio in TG signifies accelerated podocyte loss. The mechanisms that lead to podocyte injury in TG remain unclear. We report that IgG from kidney transplant recipients with TG, but not from those without TG, cause a reduction in the expression of nephrin, significant podocyte actin cytoskeleton, and motility changes. These changes are preceded by increased expression of calcium/calmodulin kinase IV (CAMK4). Mechanistically, we found that CAMK4 phosphorylates GSK3β (glycogen synthase kinase 3 beta), activates the Wnt pathway and stabilizes the nephrin transcriptional repressor SNAIL. Silencing neonatal Fc Receptor (FcRn) or CAMK4 prevented the podocyte-damaging effects of IgG from patients with TG. Furthermore, we show that removal of N-linked glycosyl residues from these IgG did not interfere with its entry into the podocytes but eliminated its ability to upregulate CAMK4 and cause podocyte injury. The translational value of these findings is signified by the fact that CAMK4 is increased in podocytes of patients with TG but not in those without TG despite other forms of renal dysfunction. Our results offer novel considerations to limit podocyte injury in patients with kidney transplants, which may lead to eventual glomerular destabilization and transplant glomerulopathy.
登录
查看更多内容
影响因子：
7.3
作者：
Dekkers G;Rispens T;Vidarsson G
通讯作者：
Vidarsson G
影响因子：
4.1
作者：
An GH;Yun J;Hong YA;Khvan M;Chung BH;Choi BS;Park CW;Choi YJ;Kim YS;Yang CW
通讯作者：
Yang CW
DOI：
10.1002/art.39499
发表时间：
2016-04
期刊：
Arthritis & rheumatology (Hoboken, N.J.)
影响因子：
--
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
通讯作者：
Tsokos GC
影响因子：
5
作者：
Matsui, Isao;Ito, Takahito;Hori, Masatsugu
通讯作者：
Hori, Masatsugu
影响因子：
13.6
作者：
Delville, Marianne;Lamarthee, Baptiste;Anglicheau, Dany
通讯作者：
Anglicheau, Dany