Toll-like Receptor 4 Signaling Pathway in the Protective Effect of Pioglitazone on Experimental Immunoglobulin A Nephropathy

摘要

Background:In vitro experiments have revealed that toll-like receptor 4 (TLR4) pathway is involved in the progression ofimmtnoglobulin A nephropathy (IgAN) by induction of proinflammatory cytokines.Evidence showed that,in other disease models,peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists have been shown to exert anti-inflammatory effects through suppression of the expression and activity of TLR4.However,the interaction between PPAR-γ and TLR4 in IgAN has not been fully studied both in vitro and in vivo.In this study,we explored whether TLR4 pathway attributed to the progression of IgAN in experimental rats.Methods:Bovine gamma globulin was used to establish IgAN model.Fifty-four Lewis rats were randomly divided into six groups:ControlTAK242,IgANTAK242,toll-like receptor 4 inhibitor (TAK242) groups (rats were administrated with TLR4 inhibitor,TAK242) and ControlPio,IgANPio,Pio groups (rats were administrated with PPAR-γ agonist,pioglitazone).Urinary albumin-to-creatinine ratio (ACR),serum creatinine,and blood urea nitrogen were detected by automatic biochemical analyzer.Renal histopathological changes were observed after hematoxylin-eosin staining,and the IgA deposition in glomeruli was measured by immunofluorescence staining.Real-time polymerase chain reaction and Western blotting were used to detect TLR4 and interleukin-1 beta (IL-1 β) message ribonucleic acid (mRNA) and protein expression in renal tissues.Results were presented as mean ± standard deviation.Differences between groups were analyzed by one-way analysis of variance.Results:Compared to normal rats,experimental rats showed higher ACR (4.45 ± 1.33 mg/mmol vs.2.89 ± 0.96 mg/mmol,P ＜ 0.05),obvious IgA deposition with mesangial hypercellularity,hyperplasia of mesangial matrix accompanied by increased serum IL-1β (48.28 ± 13.49 pg/ml vs.35.56 ± 7.4 l pg/ml,P ＜ 0.05),and renal expression of IL-1β and TLR4.The biochemical parameters and renal pathological injury were relieved in both TAK242 group and Pio group.The expressions of renal tissue TLR4,IL-1β,and serum IL-1 β were decreased in rats treated with TAK242,and the expression ofTLR4 mRNA and protein was significantly reduced in Pio group compared to IgANPio group (1.22 ± 0.28 vs.1.72 ± 0.45,P ＜ 0.01,and 0.12 ± 0.03 vs.0.21 ± 0.05,P ＜ 0.01).Conclusions:Our study proves that inflammation mediated by TLR4 signaling pathway is involved in the progression of IgAN in rat models.Moreover,pioglitazone can inhibit the expression of TLR4 in IgAN.