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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

 12M15M15M+L15M+L+PDTC
BW383±4378±15370±16369±15
TCP148±5135±5a123±3a129±3a
ALB27±575±1876±2932±14b
Scr0.5±0.10.7±0.3a0.6±0.10.6±0.1
GS%2.6±0.88.8±1.7a5.0±1.92.4±0.9b
Coll-1%4.4±0.59.8±0.2a6.2±0.2a5.3±0.2abc
AII+5±17±15±15±1b
25±169±6a47±3b35±6b
TLR41.0±0.11.5±0.31.1±0.10.8±0.1b
IL-61.0±0.12.0±0.3a2.1±0.31.1±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.