Abstract: TH-PO031

Inhibition of the TLR4/NF-κB Axis Attenuated Glomerular Inflammation and Injury in Long Term Experimental Diabetic Kidney Disease

Session Information

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

  • Foresto-Neto, Orestes, University of Sao Paulo, Sao Paulo, Brazil
  • Machado, Flavia G, University of Sao Paulo, Sao Paulo, Brazil
  • Malheiros, Denise M., University of Sao Paulo, Sao Paulo, Brazil
  • Camara, Niels OS, University of Sao Paulo, Sao Paulo, Brazil
  • Fujihara, Clarice K., University of Sao Paulo, Sao Paulo, Brazil
  • Zatz, Roberto, University of Sao Paulo, Sao Paulo, Brazil
  • Albino, Amanda H., University of Sao Paulo, Sao Paulo, Brazil
  • Arias, Simone C A, University of Sao Paulo, Sao Paulo, Brazil
  • Faustino, Viviane D., University of Sao Paulo, Sao Paulo, Brazil
  • Avila, Victor F, University of Sao Paulo, Sao Paulo, Brazil
  • Sena, Claudia R., University of Sao Paulo, Sao Paulo, Brazil
  • Fanelli, Camilla, University of Sao Paulo, Sao Paulo, Brazil
  • Viana, Vivian L, University of Sao Paulo, Sao Paulo, Brazil
  • Cenedeze, Marcos A, University of Sao Paulo, Sao Paulo, Brazil
Background

The TLR4/NF-κB signaling pathway promotes the transcription of inflammatory interleukin genes. There is evidence that activation of this innate immunity pathway is involved in the pathogenesis of diabetic kidney disease (DKD). We investigated whether NF-κB inhibition with pyrrolidinedithiocarbamate (PDTC) exerts long term renoprotection in experimental DKD.

Methods

Diabetes (DM) was induced in 27 Munich-Wistar rats by a single streptozotocin injection (65 mg/kg, iv). Blood glucose (BG) was kept between 300 and 400 mg/dL with daily NPH insulin. Rats were divided into Groups DM (untreated) and DM+PDTC (receiving PDTC, 60 mg/kg/day vo). Untreated nondiabetic rats (C, n=12) were also studied. After 12 months, we assessed: urinary albumin/creatinine (Ualb/Ucr); kidney/body weight (KW/BW); glomerular sclerosis (GS, %); glomerular zonula occludens-1 (gZO-1, %); glomerular macrophage infiltration (gMΦ, cells/mm2); glomerular TLR4, IL-1β and NLRP3 positive staining (%), renal content of heme oxigenase-1 (HO-1) and nuclear p65 (NF-κB) (fold change).

Results

After 12 months, the untreated DM group exhibited high Ualb/Ucr, renal hypertrophy, high GS, loss of gZO-1, and more intense gMΦ than C. gTLR4 and NF-κB were activated in association with increased gIL-1β and HO-1 content, whereas gNLRP3 was similar to the C value. PDTC treatment inhibited NF-κB activation and prevented the augmentation of the gTLR4, gIL-1β and HO-1 contents. In addition, PDTC attenuated renal hypertrophy and prevented the increase in Ualb/Ucr, GS, gMΦ, as well as the loss of gZO-1, without interfering with BG.

Conclusion

TLR4/NF-κB inhibition with PDTC exerts glomerular protection in long-term DKD, without changing the abundance of the NLRP3 inflammasome. These findings suggest a specific involvement of the TLR4/NF-κB axis in the pathogenesis of DKD and the possibility that this signaling pathway becomes a therapeutic target. FAPESP/CNPq

 BGUalb/UcrKW/BWGSgZO-1gMΦgTLR4NF-κBgIL-1βHO-1gNLRP3
C98±21.5±0.20.5±0.02.6±0.477±116±31±01.0 ±0.310±11.0±0.11.4±0.2
DM378±24a5.1±1.2a0.7±0.0a7.9±1.9a61±2a54±15a3±0a3.6±0.5a25±2a2.3±0.4a1.4±0.4
DM+PDTC386±7a1.3±0.3b0.6±0.0ab2.1±0.7b75±2b33±10b1±0b1.7±0.3b13±1b1.4±0.2b1.2±0.2

Mean±SE; ap<0.05 vs C, bp<0.05 vs DM.

Funding

  • Government Support - Non-U.S.