Abstract: SA-PO835
NF-κB Inhibition During Short-Term LNAME and Salt Overload Strongly Attenuates the Late Development of CKD
Session Information
- Molecular Mechanisms of CKD - III
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 1903 CKD (Non-Dialysis): Mechanisms
Authors
- Oliveira, Karin C., University of Sao Paulo, Sao Paulo, Brazil
- Zambom, Fernanda FF, University of Sao Paulo, Sao Paulo, Brazil
- Albino, Amanda H., 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
- 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
Background
Brief NO inhibition by LNAME + high-salt diet (HS) results in marked hypertension (HT) and renal injury that abate upon treatment interruption but evolve to CKD along ensuing months. Activation of the NLRP3 and NF-κB pathways may participate in this process. Here we investigated whether NF-κB inhibition during LNAME+HS would prevent the acute and/or chronic effects of this treatment.
Methods
Male Munich-Wistar rats (N=11) received oral LNAME+HS. A second group (N=12) received in addition the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC), 60 mg/kg/day vo. Control rats (C) received HS only (N=10). All treatments were ceased at 4 wks. Assessed at 4, 8 and 24 wks were: tail-cuff pressure (TCP, mmHg), albuminuria (ALB, mg/d), glomerulosclerosis (GS, %), interstitial collagen-1 (COLL, %), infiltration (cells/mm2) by macrophages (MΦ), lymphocytes (Ly) , angiotensin 2+ (Ang2+) and NLRP3+ cells, and the renal abundance (x HS) of IL1β (pg/mg), nuclear p65 (NFκB), Casp1, TLR4, and IL-6.
Results
At 4 wks, HS+LNAME caused severe hypertension, ALB, GS, COLL, MΦ/Ly/Ang2+-cell infiltration and activation of the TLR4/NFκB/IL6 and NLRP3/Casp1/IL1β pathways, all of which were prevented or strongly attenuated by PDTC. Partial regression at 8wks was followed by progression to CKD at 28 wks, also largely prevented by early PDTC.
Conclusion
Early NF-κB activation is essential for subsequent autonomous activation of innate immunity and progression to CKD in this model, and may be the basis for future therapeutic strategies. FAPESP/CNPq
| 4wks | 8wks | 28wks | |||||||
| C | HS+LNAME | HS+LNAME+PDTC | C | HS+LNAME | HS+LNAME+PDTC | C | HS+LNAME | HS+LNAME+PDTC | |
| TCP | 146±3 | 213±4* | 192±5*# | 146±3 | 164±4* | 157±3 | 131±2 | 166±7* | 158±4 |
| ALB | 8±2 | 151±24* | 51±17*# | 5±1 | 25±6* | 7±2# | 16±3 | 74±13* | 42±12# |
| GS% | 0.1±0.1 | 3±1* | 2±1* | 0.1±0.1 | 1±1* | 1±1# | 1±1 | 8±2* | 3±1# |
| COLL | 1±1 | 4±1* | 1±1# | 2±1 | 4±1* | 2±1# | 1±1 | 4±1* | 1±1# |
| MΦ | 29±4 | 255±27* | 81±14# | 33±5 | 82±12* | 80±10* | 35±4 | 98±14* | 49±6# |
| Ly | 43±8 | 231±21* | 34±7# | 52±6 | 116±13* | 29±6*# | 39±6 | 138±13* | 26±5# |
| Ang2 | 2±1 | 10±1* | 4±1# | 3±1 | 14±2* | 5±1# | 3±1 | 12±2* | 3±1# |
| TLR4 | 1.0±0.1 | 3.1±0.5* | 1.8±0.6# | 1.0±0.1 | 3.2±0.5* | 1.3±0.4# | 1.0±0.1 | 2.9±0.4* | 1.4±0.4# |
| NF-kB | 1.0±0.2 | 4.4±0.7* | 1.6±0.2# | 1.0±0.1 | 2.6±0.4* | 1.5±0.1*# | 1.0±0.1 | 2.7±0.4* | 0.4±0.1*# |
| IL-6 | 1.0±0.1 | 3.2±0.6* | 2.1±0.2* | 1.0±0.1 | 4.7±0.5* | 1.9±0.3# | 1.0±0.1 | 3.3±1.0* | 1.1±0.3# |
| NLRP3 | 1.0±0.1 | 4.5±0.5* | 0.6±0.2# | 1.0±0.1 | 3.7±0.7* | 1.1±0.4# | 1.1±0.2 | 4.5±0.9* | 0.8±0.2# |
| Casp1 | 1.0±0.2 | 4.1±0.7* | 2.1±0.6# | 1.0±0.1 | 2.4±0.5* | 1.0±0.2# | 1.0±0.1 | 2.5±0.8 | 1.4±0.5 |
| IL-1β | 2.2±0.3 | 4.1±0.6* | 2.6±0.4 | 1.8±0.2 | 3.2±0.5* | 2.6±0.4* | 1.0±0.2 | 4.7±0.4* | 2.6±0.8 |
Mean±SE; *p<0.05 vs HS; #p<0.05 vs HS+LNAME
Funding
- Government Support - Non-U.S.