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Abstract: SA-PO604

TLR3 Activation Contributes to Pathogenesis of Mesangial Proliferative Glomerulonephritis

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Watanabe, Syuhei, Department of Cell Biology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
  • Zhang, Ying, Department of Cell Biology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
  • Yasuda, Hidenori, Department of Cell Biology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
  • Fukusumi, Yoshiyasu, Department of Cell Biology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
  • Kazama, Junichiro James, Fukushima Medical University, Fukushima, Japan
  • Kawachi, Hiroshi, Department of Cell Biology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
Background

It is assumed that Toll-like receptor (TLR) is activated by ligands released from damaged tissue, and the TLR-mediated signaling is involved in the development of mesangial proliferative glomerulonephritis (MGN). However, how TLR detects signals from the damaged tissue and the pathogenic mechanism initiated by the TLR activation in MGN are poorly understood. Thy1.1. GN, a widely used rat experimental model for MGN, is caused by the injection of the antibody against Thy1.1 expressed on mesangial cell surface. Thy1.1.GN is characterized by diffuse mesangiolysis at 24h and consequent accumulation of inflammatory cells and mesangial cell proliferation.

Methods

The kinetics of the expression of TLR2, TLR3, TLR4 in Thy1.1. GN were analyzed by RT-PCR and immune-histochemical analyses. The cells expressing TLRs were analyzed.

Results

The increase in mRNA expression of TLR3 was already detected at 1 h (3.4 times to control) and the increase is promoted on day 7 (11.4 times to control). However, such a clear increase is not detected in TLR2 or TLR4. Immunostaining of TLR3 was not detected in normal glomeruli, and the clear positive staining of TLR3 was detected at mesangial area at 1h, and at 24h and day 7 the positive staining was detected at the expanded mesangial area and in capillary lumen. In Thy1.1. GN at the early recovery phase after mesangiolysis Thy1.1. negative cells were mainly accumulated in mesangial area and the population of Thy1.1 positive cells gradually increased with time. ED1+ macrophage (4.3±0.45/glom.), ED3+ activated macrophages (4.5±0.90/glom) and NKRP1+ NK cells (1.6±0.45/glom) were accumulated in glomeruli on day 7 of Thy1.1. GN. Dual labeling immune-histochemical analysis showed that TLR3 was detected on Thy1.1. negative cells localized at mesangial area but not detected on Thy1.1. positive cell, and some portions of ED3+ cells express TLR3 but no NKRP1+ cells express TLR3. mRNA expression IFN-β, which is mainly activated by TRL3-mediated signaling, was increased (2.8 times to control) in this GN model.

Conclusion

Not TLR2 or TLR4 but TLR3 was dominantly activated in Thy1.1. GN. It is conceivable that TLR3 responds to molecules released by damaged mesangial cell, and TLR3-mediated signaling participates in the pathogenesis of mesangial proliferative nephritis.

Funding

  • Government Support - Non-U.S.