Abstract: TH-PO032

Glomerular Mechanical Tension Promotes Activation of the NLRP3 Inflammasome Pathway in Experimental Diabetic Kidney Disease: Role of Podocytes

Session Information

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

  • Arias, Simone C A, Univ of Sao Paulo, Sao Paulo, Brazil
  • Vellosa, Matheus T, Univ of Sao Paulo, Sao Paulo, Brazil
  • Faustino, Viviane D., Univ of Sao Paulo, Sao Paulo, Brazil
  • Avila, Victor F, Univ of Sao Paulo, Sao Paulo, Brazil
  • dos Reis, Luciene, Univ of Sao Paulo, Sao Paulo, Brazil
  • Malheiros, Denise M., Univ of Sao Paulo, Sao Paulo, Brazil
  • Camara, Niels OS, Univ of Sao Paulo, Sao Paulo, Brazil
  • Fujihara, Clarice K., Univ of Sao Paulo, Sao Paulo, Brazil
  • Zatz, Roberto, Univ of Sao Paulo, Sao Paulo, Brazil
Background

We showed previously (ASN 2016) that in the 5/6 ablation the estimated glomerular capillary mechanical tension (GCMT) was increased along with activation of the TLR4/NLRP3/CASP1/IL1β innate immunity (InIm) axis, helping to explain the link between hemodynamic insult and glomerular inflammation. Here we investigated whether such effect of cell agression also manifests in streptozotocin diabetes mellitus (DM), and the possible role of podocytes in this response.

Methods

We analyzed retrospectively, by immunohistochemistry, renal tissue from male Munich-Wistar rats divided into Control (C), Uninephrectomy (UNx) and UNx+DM groups. Mean arterial pressure (MAP, mmHg) had been measured 60 days after DM induction, whereas GCMT (mmHg×μm) was estimated from glomerular pressures and mean glomerular radii. Glomerular infiltration by macrophages (MΦ, cells/mm2) was also assessed. The protein content of TLR4, NLRP3, CASP1, and IL-1β was evaluated in DM glomeruli (% area), as well as in cultured murine podocytes in the presence or absence of 15% stretching.

Results

In UNX, MAP was elevated without change in GCMT or Inlm components. In UNx+DM, hypertension was associated with increased GCMT, MΦ and InIm components, whereas a positive correlation was observed between NLRP3 and IL-1β. Under stretching, the protein content of ERK 1/2 was increased in endothelial cells, mesangial cells and podocytes. However, only podocytes exhibited a significant effect of stretching regarding the TLR4/NLRP3/CASP1/IL1β axis.

Conclusion

Inlm activation may mediate the inflammatory effects of GCMT, thus participating in the initiation and perpetuation of progressive glomerular injury in both diabetic and nondiabetic kidney disease. FAPESP/CNPq.

 MAPGCMTTLR4NLRP3CASP1IL-1β
C (n=10)113±2146±41.1±0.20.3±0.10.9±0.60.3±0.11.2±0.3
UNx (n=6)123±3a164±51.9±0.2a1.4±0.3a0.5±0.20.9±0.21.8±0.8
UNx+DM (n=5)126±4a225±11ab3.1±0.2ab1.9±0.3a2.4±0.6ab1.9±0.3ab5.3±2.4a

Mean±SE. ap<0.05 vs C; bp<0.05 vs UNx

Funding

  • Government Support - Non-U.S.