Abstract: FR-PO387
Combined Treatment with Losartan and an NF-κB Inhibitor Affords Better Renoprotection Than AT1R Blockade Alone in Aging Rats
Session Information
- CKD: Mechanisms - II
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Tessaro, Helena Mendonca, Univ of Sao Paulo, Sao Paulo, Brazil
- Zambom, Fernanda FF, Univ of Sao Paulo, Sao Paulo, Brazil
- Ribeiro, Sara C F, Univ of Sao Paulo, Sao Paulo, Brazil
- Faustino, Viviane D., Univ of Sao Paulo, Sao Paulo, Brazil
- Pião, Janice, Univ of Sao Paulo, Sao Paulo, Brazil
- Malheiros, Denise M., Univ of Sao Paulo, Sao Paulo, Brazil
- Camara, Niels Olsen Saraiva, Univ of Sao Paulo, Sao Paulo, Brazil
- Fujihara, Clarice K., Univ of Sao Paulo, Sao Paulo, Brazil
- Foresto-Neto, Orestes, Univ of Sao Paulo, Sao Paulo, Brazil
- Zatz, Roberto, Univ of Sao Paulo, Sao Paulo, Brazil
Background
The mechanisms underlying aging nephropathy (AN) are unclear. Renal angiotensinII (AII) and NF-κB activation are important factors in the pathogenesis of Chronic Kidney Disease (CKD). We investigated whether combined treatment with Losartan (L) and the NF-κB inhibitor Pyrrolidine Dithiocarbamate (PDTC) would attenuate experimental AN.
Methods
Male Munich-Wistar rats were divided in 4 groups: 12M (n=10), 12-month-old rats; 15M (n=10), 15-month-old rats; 15M+L(n=8) rats receiving L (50 mg/kg/d) and 15M+L+PDTC (n=8), rats receiving L and PDTC (15 mg/kg/d). Both compounds were given orally from 12 to15 mo of age. We assessed body weight (BW, g), tail-cuff pressure (TCP, mmHg), albuminuria (ALB, mg/24h), serum creatinine (Scr, mg/dL), glomerulosclerosis (GS,%), cortical macrophages (MΦ, cells/mm2) and AII+ (cells/mm2), Collagen-1 (Coll-1, %), as well as renal TLR4 and IL-6 (WB).
Results
Group 15M exhibited mild hypotension, creatinine retention, albuminuria, glomerulosclerosis, Coll-1 deposition and cortical infiltration by MΦ. Renal abundance of TLR4 and IL-6 was also increased, suggesting activation of the NF-κB pathway. L decreased cortical MΦ and Coll-1, but not TLR4 or IL-6, failing to reduce ALB or GS%. Combined L+PDTC prevented the increase of renal TLR4, IL-6 and MΦ, reduced AII+ and strongly attenuated ALB and GS%.
Conclusion
Simultaneous inhibition of renal AII and of the NF-κB system can contribute to reduce the decline of renal function with age. FAPESP/CNPq
12M | 15M | 15M+L | 15M+L+PDTC | |
BW | 383±4 | 378±15 | 370±16 | 369±15 |
TCP | 148±5 | 135±5a | 123±3a | 129±3a |
ALB | 27±5 | 75±18 | 76±29 | 32±14b |
Scr | 0.5±0.1 | 0.7±0.3a | 0.6±0.1 | 0.6±0.1 |
GS% | 2.6±0.8 | 8.8±1.7a | 5.0±1.9 | 2.4±0.9b |
Coll-1% | 4.4±0.5 | 9.8±0.2a | 6.2±0.2a | 5.3±0.2abc |
AII+ | 5±1 | 7±1 | 5±1 | 5±1b |
MΦ | 25±1 | 69±6a | 47±3b | 35±6b |
TLR4 | 1.0±0.1 | 1.5±0.3 | 1.1±0.1 | 0.8±0.1b |
IL-6 | 1.0±0.1 | 2.0±0.3a | 2.1±0.3 | 1.1±0.1bc |
Mean±SE;ap<0.05 vs 12M, bp<0.05 vs 15M, cp<0.05 vs 15M+L
Funding
- Government Support - Non-U.S.