Department of Nephrology, The First Affiliated Hospital of University of South China, Hengyang, China.
Department of Nephrology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
Transplantation. 2021 Apr 1;105(4):757-767. doi: 10.1097/TP.0000000000003446.
Chronic renal allograft dysfunction (CRAD) is a major condition that impedes the long-term survival of renal allografts. However, the mechanism of CRAD is obscure, and the effective strategies for controlling the progression of CRAD are lacking. The present study used a CRAD rat model to assess the effect of glycogen synthase kinase 3β (GSK-3β) inhibition on the development of CRAD.
A classical F334-to-LEW orthotopic renal transplantation was performed on the CRAD group. The treatment group was treated with the GSK-3β inhibitor 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione for 12 consecutive weeks following renal transplantation. The study included uninephrectomized F344 and Lewis rats as control subjects. Twelve weeks post surgery, the rats were retrieved for analysis of renal function, urine protein levels, histological, immunohistochemical, and molecular biological parameters.
Administration of 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione inactivated GSK-3β and thereby improved renal function, attenuated proteinuria, and reduced renal tissue damage in CRAD rats. Besides, inactivation of GSK-3β inhibited nuclear factor-κB activation, macrophage infiltration, and expression of multiple proinflammatory cytokines/chemokines. Inhibition of GSK-3β also decreased the levels of malondialdehyde, increased superoxide dismutase levels, upregulated the expression of heme oxygenase-1 and NAD(P)H quinone oxidoreductase-1, and enhanced nuclear translocation of nuclear factor erythroid 2-related factor 2 in the kidneys of CRAD rats.
Inhibition of GSK-3β attenuates the development of CRAD by inhibiting inflammation and oxidant stress. Thus, GSK-3β inhibition may represent a potential therapeutic strategy for the prevention and treatment of CRAD.
慢性移植肾失功（CRAD）是阻碍肾移植长期存活的主要因素。然而，CRAD 的发病机制尚不清楚，缺乏控制 CRAD 进展的有效策略。本研究采用 CRAD 大鼠模型评估糖原合成酶激酶 3β（GSK-3β）抑制对 CRAD 发展的影响。
对 CRAD 组进行经典的 F334 至 LEW 原位肾移植。移植后，治疗组连续 12 周给予 GSK-3β抑制剂 4-苄基-2-甲基-1,2,4-噻二唑烷-3,5-二酮治疗。研究包括单侧肾切除的 F344 和 Lewis 大鼠作为对照。手术后 12 周，回收大鼠进行肾功能、尿蛋白水平、组织学、免疫组织化学和分子生物学参数分析。
4-苄基-2-甲基-1,2,4-噻二唑烷-3,5-二酮可使 GSK-3β失活，从而改善 CRAD 大鼠的肾功能，减轻蛋白尿，减轻肾组织损伤。此外，GSK-3β 的失活抑制了核因子-κB 的激活、巨噬细胞浸润和多种促炎细胞因子/趋化因子的表达。GSK-3β 的抑制还降低了丙二醛的水平，增加了超氧化物歧化酶的水平，上调了血红素加氧酶-1 和 NAD（P）H 醌氧化还原酶-1 的表达，并增强了核因子红细胞 2 相关因子 2 在 CRAD 大鼠肾脏中的核转位。
GSK-3β 的抑制通过抑制炎症和氧化应激来减轻 CRAD 的发展。因此，抑制 GSK-3β 可能是预防和治疗 CRAD 的潜在治疗策略。
