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

Abstract

Background:In vitro experiments have revealed that toll-like receptor 4 (TLR4) pathway is involved in the progression of immunoglobulin 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-1β) 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 ± 7.41pg/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-1β were decreased in rats treated with TAK242, and the expression of TLR4 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.

Does the renal expression of Toll-like receptors play a role in patients with IgA nephropathy?

“…In vitro experiments revealed that TLR 4 pathway may be involved in the progression of IgAN through induction of transcription factors, mainly NF-κB and proinflammatory cytokines. An experimental rat model showed that peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists (e.g., pioglitazone) exert anti-inflammatory effects through suppression of the expression and activity of TLR 4 (18). In agreement with the findings from the rat model, in our study we found elevated intrarenal staining of TLR 4 in tissues of patients with IgAN with proteinuria >1g/day as well as those with renal insufficiency (Table 4).…”

“…Our results for the first time showed expression of TLR proteins in renal tissue of patients with IgAN, thus extending earlier observations on elevated levels of TLR mRNAs in PBMCs from patients with IgAN and associations of specific TLR 9 polymorphisms with disease progression in Japanese patients (11,(15)(16)(17)(18)(19). In IgAN patients, expression levels of TLR 2, 3, 5, or 9 in PBMC correlated with proteinuria and TLR 4 mRNA expression was associated with proteinuria and microscopic hematuria (11).…”

Crosstalk between Peroxisome Proliferator-Activated Receptors andToll-Like Receptors: A Systematic Review

“…They showed that administration of pioglitazone regulated the TLR-4-related inflammation in IgAN. 36…”

Anti-influenza A Virus Effects and Mechanisms of Emodin and Its Analogs via Regulating PPARα/γ-AMPK-SIRT1 Pathway and Fatty Acid Metabolism

“…Activation of PPAR α can inhibit NF- κ B by enhancing the expression of I κ B α or directly binding to RelA/p65 protein [ 23 ]. Activation of PPAR γ can inhibit the expressions of TLR4 and NADPH oxidase p47phox [ 24 ] and antagonize the inflammatory pathways such as NF- κ B, AP1, and STAT in respiratory virus infections [ 25 ]. AMPK activation can inhibit oxidative stress and airway inflammation in mice [ 26 ].…”