Abstract: SA-PO329

NLRP3 Inflammasome Inhibition Ameliorates Tubulointerstitial Injury in the Remnant Kidney Model

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Foresto-Neto, Orestes, University of Sao Paulo, Sao Paulo, Brazil
  • Malheiros, Denise M., University of Sao Paulo, Sao Paulo, Brazil
  • Abensur, Hugo, University of Sao Paulo, Sao Paulo, Brazil
  • Camara, Niels OS, University of Sao Paulo, Sao Paulo, Brazil
  • Zatz, Roberto, University of Sao Paulo, Sao Paulo, Brazil
  • Fujihara, Clarice K., University of Sao Paulo, Sao Paulo, Brazil
  • Avila, Victor F, University of Sao Paulo, Sao Paulo, Brazil
  • Arias, Simone C A, University of Sao Paulo, Sao Paulo, Brazil
  • Zambom, Fernanda FF, University of Sao Paulo, Sao Paulo, Brazil
  • Rempel, Lisienny CT, University of Sao Paulo, Sao Paulo, Brazil
  • Machado, Flavia G, University of Sao Paulo, Sao Paulo, Brazil
  • Fanelli, Camilla, University of Sao Paulo, Sao Paulo, Brazil
  • Sena, Claudia R., University of Sao Paulo, Sao Paulo, Brazil
  • Viana, Vivian L, University of Sao Paulo, Sao Paulo, Brazil
Background

We showed previously that NF-κB signaling inhibition attenuates renal injury and inflammation in the 5/6 renal ablation (Nx) model (AJPRenal, 2007). We subsequently showed that the NLRP3 inflammasome, another innate immunity pathway, is also activated in Nx (SciRep, 2017). There is evidence that the xanthine oxidase (XO) inhibitor allopurinol (ALLO) inhibits NLRP3 activation. We investigated whether NLRP3 inhibition by ALLO exerts renoprotection in Nx.

Methods

Munich-Wistar rats (N=33) underwent Nx or sham operation (S, N=16). Nx rats were divided in: Nx, untreated, and Nx+ALLO, given ALLO 36 mg/kg/day vo. On day 60, tail-cuff pressure (TCP, mmHg), urinary NGAL (uNGAL, mg/24h), interstitial collagen 1 (COL, %) and macrophages (MΦ, cells/mm2), renal XO activity (rXO, μU/mg), renal uric acid (rUA, mg/g) and renal content of heme oxygenase 1 (HO-1), superoxide dismutase 2 (SOD2), caspase 1 (CASP1) and nuclear p65 (NF-κB) (fold increase x C), IL-1β (pg/mg), and interstitial NLRP3 (cells/ mm2) were assessed.

Results

ALLO normalized rXO activity and prevented rUA and oxidative stress enhancement in Nx. ALLO also attenuated hypertension and promoted selective tubulointerstitial protection, reducing uNGAL, COL and MΦ. ALLO reduced the renal content of the inflammasome components (NLRP3, CASP1 and IL-1β), but not the NF-κB activation.

Conclusion

In view of its antiinflammatory, antioxidant and renoprotective effects, ALLO may help to prevent the progression of CKD. FAPESP/CNPq

 SNxNx+ALLO
TCP134±2212±8a191±6ab
uNGAL29±448±5a32±3b
COL2±09±1a5±1ab
22±2187±26a130±20ab
rXO70±5116±7a69±5b
rUA1.3±0.12.3±0.1a1.3±0.2b
HO-11.0±0.65.4±1.2a2.9±0.5b
SOD21.0±0.10.7±0.1a1.1±0.2b
NLRP30.7±0.45.0±0.4a2.8±0.5ab
CASP11.0±0.12.5±0.2a1.8±0.3ab
IL-1β1.6±0.14.7±0.6a2.3±0.3b
NF-κB1.0±0.13.2±0.4a3.7±0.6a

Mean±SE. ap<0.05 vs S, bp<0.05 vs Nx+ALLO.

Funding

  • Government Support - Non-U.S.