GSK-3β Inhibitor Induces Expression of the TLR4/MyD88/NF-κB Signaling Pathway to Protect Against Renal Ischemia-Reperfusion Injury During Rat Kidney Transplantation

Shuai Su, Peng Zhang, Qilin Zhang, Zhikang Yin
Inflammation 2019 August 22
Ischemia-reperfusion injury (IRI) is an inevitable consequence of kidney transplantation (KT). The aim of our study was to investigate the protective effect of a glycogen synthase kinase 3β (GSK-3β) inhibitor against cold IRI in a rat renal transplantation (RT) model and a rat cold-IRI model through the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor κ-light-chain-enhancer of the activated B cell (NF-κB) signaling pathway. We treated Sprague Dawley (SD) rats in the RT and cold-IRI models with 5 mg/kg and 1 mg/kg, respectively, of the GSK-3β inhibitor 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8). We then measured inflammatory factors, i.e., tumor necrosis factor alpha (TNF-α) and interleukins-1β and IL-6 (IL-1β, IL-6), as well as oxidative stress markers, i.e., superoxide dismutase (SOD) and malondialdehyde (MDA), in serum and kidneys. Renal function tests and pathological examinations were performed at 0, 1, 2, 3, and 7 days after RT or cold IRI. We measured expression of TLR4, MyD88, inhibitor of NF-κB kinase (IκB), phosphorylated IκB (p-IκB), NF-κB p65, p-p65, GSK-3β, and phosphorylated GSK-3β (p-GSK-3β) by Western blot and immunohistological staining. After intervention with the GSK-3β inhibitor, renal function was improved; oxidative stress injury was reduced; expression of p-GSK-3β was upregulated; expression of p-IκB, TLR4, MyD88, and p-p65 was downregulated; pathological damage was significantly reduced; and expression of TNF-α, IL-1β, and IL-6 messenger ribonucleic acid (mRNA) was downregulated. These results strongly suggested that GSK-3β might be a key target for the treatment of IRI in KT. The GSK-3β inhibitor inhibited phosphorylation of NF-κB p65 and IκB by inhibiting the TLR/MyD88 pathway, reducing oxidative stress injury and the production of downstream inflammatory factors.

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