Inhibition of Glycogen Synthase Kinase 3β Alleviates Chronic Renal Allograft Dysfunction in Rats
Inhibition of Glycogen Synthase Kinase 3β Alleviates Chronic Renal Allograft Dysfunction in Rats
复制标题
糖原合酶激酶 3β 的抑制可减轻大鼠慢性同种异体移植肾功能障碍
DOI：
10.1097/tp.0000000000003446
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发表时间：
2021-04-01
期刊：
影响因子：
6.2
通讯作者：
Zou, Hequn
中科院分区：
文献类型：
--
作者：
Deng, Jin;Wang, Xin;Zou, Hequn
慢性移植肾功能不全（CRAD）是影响移植肾长期存活的主要因素。然而，CRAD的发病机制尚不清楚，缺乏有效的控制CRAD进展的策略。本研究采用CRAD大鼠模型评估糖原合成酶激酶3 β（GSK-3 β）抑制剂对CRAD发展的影响。方法：对CRAD组进行经典的F334-to-LEW原位肾移植。治疗组在肾移植术后给予GSK-3 β抑制剂4-苄基-2-甲基-1，2，4-噻二唑烷-3，5-二酮连续治疗12周。该研究包括单侧肾切除的F344和刘易斯大鼠作为对照受试者。手术后12周，大鼠被检索分析肾功能，尿蛋白水平，组织学，免疫组织化学和分子生物学parameters.Results.Administration的4-苄基-2-甲基-1，2，4-噻二唑烷-3，5-二酮失活GSK-3 β，从而改善肾功能，衰减蛋白尿，并减少肾组织损伤CRAD大鼠。此外，GSK-3 β的失活抑制核因子-κ B活化、巨噬细胞浸润和多种促炎细胞因子/趋化因子的表达。抑制GSK-3 β也降低了丙二醛的水平，增加超氧化物歧化酶的水平，上调血红素加氧酶-1和NAD（P）H醌氧化还原酶-1的表达，并增强核转位的核因子红细胞2相关因子2在肾脏的CRADrats.Conclusions。抑制GSK-3 β减弱CRADby抑制炎症和氧化应激的发展。因此，GSK-3 β抑制可能代表了预防和治疗CRAD的潜在治疗策略。
Background.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 3 beta (GSK-3 beta) inhibition on the development of CRAD.Methods.A classical F334-to-LEW orthotopic renal transplantation was performed on the CRAD group. The treatment group was treated with the GSK-3 beta 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.Results.Administration of 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione inactivated GSK-3 beta and thereby improved renal function, attenuated proteinuria, and reduced renal tissue damage in CRAD rats. Besides, inactivation of GSK-3 beta inhibited nuclear factor-kappa B activation, macrophage infiltration, and expression of multiple proinflammatory cytokines/chemokines. Inhibition of GSK-3 beta 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.Conclusions.Inhibition of GSK-3 beta attenuates the development of CRAD by inhibiting inflammation and oxidant stress. Thus, GSK-3 beta inhibition may represent a potential therapeutic strategy for the prevention and treatment of CRAD.