Inhibition of Glycogen Synthase Kinase 3β Alleviates Chronic Renal Allograft Dysfunction in Rats

Abstract

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 3β (GSK-3β) 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-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. Results. Administration of 4-benzyl-2-methyl-1,2,4thiadiazolidine-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. Conclusions. 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.

Amelioration of Renal Injury by Resveratrol in a Rat Renal Transplantation Model via Activation of the SIRT1/NF-κB Signaling Pathway

“…Assessment of oxidative stress markers and inflammatory cytokines revealed that the levels of proinflammatory cytokines, such as TNF- α , CD68, and IL-6, were higher, whereas those of GSH, SOD, and CAT were lower in transplant rats than in control groups. These results demonstrate that oxidative stress and inflammation are involved in the pathogenesis of chronic renal allograft dysfunction, which is consistent with the findings of previous studies [ 15 , 27 , 28 ]. Pharmacological intervention plays a significant role in IRI damage.…”

Safety and Efficacy of Combined Low-Dose Lithium and Low-Dose Aspirin: A Pharmacological and Behavioral Proof-of-Concept Study in Rats

“…Similarly, pretreatment with Li significantly reduced proteinuria and improved glomerular function in a mouse model of doxorubicin-or lipopolysaccharide-induced podocyte injury in mice [141]. Consistent with these findings, selective pharmacological or genetic inhibition of GSK-3β was shown to improve renal function in various models of kidney disorders in animals [142][143][144]. Support for these experimental data comes from clinical evidence indicating that chronic Li treatment leads to a slight (if any) decrease in glomerular function and a negligible incidence of CKD that are of questionable clinical significance [30,31,41,42,145].…”