Abstract: FR-PO370
Inhibition of NLRP3 Inflammasome Attenuates Renal Injury in Adriamycin Nephropathy
Session Information
- Mechanisms Associated with Kidney Fibrosis - I
November 03, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Chronic Kidney Disease (Non-Dialysis)
- 308 CKD: Mechanisms of Tubulointerstitial Fibrosis
Authors
- Faustino, Viviane D., 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
- 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
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
BW | ALB | SCr | GS | COLL | MΦ | rUA | NLRP3 | Casp1 | IL1β | SOD2 | |
C | 273±7 | 2±1 | 0.5±0.1 | 0±0 | 3±1 | 7±1 | 1±1 | 1±1 | 1.0±0.2 | 1±1 | 1.0±0.1 |
ADR | 213±9a | 391±34a | 0.6±0.1a | 3±1a | 14±1a | 218±33a | 3±1a | 4±1a | 2.4±0.5a | 3±1a | 0.6±0.1 |
ADR+Allo | 231±9a | 404±35a | 0.7±0.1a | 1±1a | 8±1ab | 42±6ab | 1±1b | 1±1b | 1.1±0.2b | 2±1ab | 1.7±0.4b |
Mean±SE, ap<0.05 vs C, bp<0.05 vs. ADR
Funding
- Government Support - Non-U.S.