title: 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 IgANPiogroup (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.
authors.affiliation: Department of Nephrology, Huadong Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Jia-Nan
authors.initials: JN
authors.lastname: Zou
authors.affiliation: Department of Nephrology, Huadong Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Nephrology, Jiangxi Provincial People's Hospital, Nanchang, Jiangxi 330006, China.
authors.forename: Sha-Sha
authors.initials: SS
authors.lastname: Hu
authors.affiliation: Department of Nephrology, Huadong Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Chen-Sheng
authors.initials: CS
authors.lastname: Fu
authors.affiliation: Department of Nephrology, Huadong Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Huadong Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Zhen-Xing
authors.initials: ZX
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Huadong Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Yi-Jun
authors.initials: YJ
authors.lastname: Lu
authors.affiliation: Department of Nephrology, Huadong Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Wei-Jun
authors.initials: WJ
authors.lastname: Chen
authors.affiliation: Department of Nephrology, Huadong Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Zhi-Bin
authors.initials: ZB
authors.lastname: Ye
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D005922:Glomerulonephritis, IGA / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D000077205:Pioglitazone; D011897:Random Allocation; D051381:Rats; D011917:Rats, Inbred Lew; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D045162:Thiazolidinediones / Q000627:therapeutic use*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D045162:Thiazolidinediones; D051197:Toll-Like Receptor 4; D000077205:Pioglitazone