Abstract: FR-PO370

Inhibition of NLRP3 Inflammasome Attenuates Renal Injury in Adriamycin Nephropathy

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Faustino, Viviane D., 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
  • Malheiros, Denise M., 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
  • Tavares, Leonardo L, University of Sao Paulo, Sao Paulo, Brazil
  • Ribeiro, Sara Cristina f, University of Sao Paulo, Sao Paulo, Brazil
  • Avila, Victor F, University of Sao Paulo, Sao Paulo, Brazil
  • Foresto-Neto, Orestes, University of Sao Paulo, Sao Paulo, Brazil
  • Zambom, Fernanda FF, University of Sao Paulo, Sao Paulo, Brazil
  • Arias, Simone C A, University of Sao Paulo, Sao Paulo, Brazil
  • Machado, Flavia G, University of Sao Paulo, Sao Paulo, Brazil
  • Sena, Claudia R., University of Sao Paulo, Sao Paulo, Brazil
Background

Innate immunity is activated in proteinuric models, and may contribute to long term interstitial fibrosis. We investigated whether the NLRP3 inflammasome pathway is involved in the pathogenesis of CKD in the adriamycin (ADR) model.

Methods

Adult male Munich-Wistar rats were given ADR (5 mg/kg iv) and either no therapy or Allopurinol (Allo), used as a NLRP3 inhibitor, 36 mg/kg/day (ADR+Allo). Control rats (C) received saline only. After 4 weeks, we assessed body weight (BW, g), albuminuria (ALB, mg/day), serum creatinine concentration (SCr, mg/dL), glomerulosclerosis (GS, %) and interstitial collagen (COLL, %), as well as infiltration by macrophages (MΦ) and by NLRP3+ cells (/mm2). The renal content (x C) of CASP1 and superoxide dismutase (SOD2), as well as that of uric acid (rUA, mg/g) and IL1β (pg/mg), were also measured.

Results

As expected, ADR promoted massive ALB, intense MΦ, GS and COLL deposition, along with increased rUA, activation of CASP1 and NLRP3, as well as evidence of oxidative stress. Allo normalized rUA and attenuated renal inflammation/fibrosis, despite the persistence of massive ALB. Likewise, Allo prevented the upregulation of NLRP3, CASP1 and IL1β. These findings were associated with an increase of the renal abundance of SOD2, suggesting an antioxidant action of Allo.

Conclusion

NLRP3/CASP1/IL1β upregulation may be a mechanism by which massive protein filtration promotes interstitial fibrosis. Inhibition of this pathway with Allo prevented the activation of this innate immunity pathway and attenuated renal injury even in the face of unabated massive proteinuria. Amelioration of rUA and oxidative stress may contribute to this beneficial effect. Allo may help to prevent or limit the progression of CKD. FAPESP/CNPq

 BWALBSCrGSCOLLrUANLRP3Casp1IL1βSOD2
C273±72±10.5±0.10±03±17±11±11±11.0±0.21±11.0±0.1
ADR213±9a391±34a0.6±0.1a3±1a14±1a218±33a3±1a4±1a2.4±0.5a3±1a0.6±0.1
ADR+Allo231±9a404±35a0.7±0.1a1±1a8±1ab42±6ab1±1b1±1b1.1±0.2b2±1ab1.7±0.4b

Mean±SE, ap<0.05 vs C, bp<0.05 vs. ADR

Funding

  • Government Support - Non-U.S.