4-benzyl-2-methyl-1-2-4-thiadiazolidine-3-5-dione and Kidney-Diseases

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.

Topics: Allografts; Animals; Anti-Inflammatory Agents; Antioxidants; Chronic Disease; Disease Models, Animal; Glycogen Synthase Kinase 3 beta; Inflammation Mediators; Kidney; Kidney Diseases; Kidney Transplantation; Male; Oxidative Stress; Protein Kinase Inhibitors; Rats, Inbred F344; Rats, Inbred Lew; Thiadiazoles

Serine-threonine protein kinase glycogen synthase kinase (GSK)-3 is involved in regulation of many cell functions, but its role in regulation of inflammatory response is unknown. Here we investigate the effects of GSK-3beta inhibition on organ injury/dysfunction caused by lipopolysaccharide or coadministration of lipopolysaccharide and peptidoglycan in the rat.. Prospective, randomized study.. University-based research laboratory.. Ninety-nine anesthetized male Wistar rats.. Study 1: Rats received either intravenous Escherichia coli lipopolysaccharide (6 mg/kg) or vehicle (1 mL/kg; saline). Study 2: Rats received either intravenous E. coli lipopolysaccharide (1 mg/kg) and Staphylococcus aureus peptidoglycan (0.3 mg/kg) or vehicle. The potent and selective GSK-3beta inhibitors TDZD-8 (1 mg/kg intravenously), SB216763 (0.6 mg/kg intravenously), and SB415286 (1 mg/kg intravenously) or vehicle (10% dimethyl sulfoxide) was administered 30 mins before lipopolysaccharide or lipopolysaccharide and peptidoglycan.. Endotoxemia resulted in increases in the serum levels of creatinine (indicator of renal dysfunction), aspartate aminotransferase, alanine aminotransferase (markers for hepatocellular injury), lipase (indicator of pancreatic injury), and creatine kinase (indicator of neuromuscular injury). Coadministration of lipopolysaccharide and peptidoglycan resulted in hepatocellular injury and renal dysfunction. All GSK-3beta inhibitors attenuated the organ injury/dysfunction caused by lipopolysaccharide or lipopolysaccharide and peptidoglycan. GSK-3beta inhibition reduced the Ser536 phosphorylation of nuclear factor-kappaB subunit p65 and the messenger RNA expression of nuclear factor-kappaB-dependent proinflammatory mediators but had no effect on the nuclear factor-kappaB/DNA binding activity in the lung. GSK-3beta inhibition reduced the increase in nuclear factor-kappaB p65 activity caused by interleukin-1 in human embryonic kidney cells in vitro.. The potent and selective GSK-3beta inhibitors TDZD-8, SB216763, and SB415286 reduced the organ injury/dysfunction caused by lipopolysaccharide or lipopolysaccharide and peptidoglycan in the rat. We propose that GSK-3beta inhibition may be useful in the therapy of the organ injury/dysfunction associated with sepsis, shock, and other diseases associated with local or systemic inflammation.

Topics: Alanine Transaminase; Aminophenols; Animals; Aspartate Aminotransferases; Blotting, Western; Cells, Cultured; Creatine Kinase; Creatinine; Endotoxemia; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Indoles; Kidney Diseases; Lipase; Lipopolysaccharides; Liver; Male; Maleimides; NF-kappa B; Peptidoglycan; Phosphorylation; Polysaccharides, Bacterial; Prospective Studies; Random Allocation; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Thiadiazoles