Pathogenic role of innate immunity in a model of chronic NO inhibition associated with salt overload

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Fregnan Zambom, Fernanda Florencia ^[1] ; Oliveira, Karin Carneiro ^[1] ; Foresto-Neto, Orestes ^[1] ; Faustino, Viviane Dias ^[1] ; Avila, Victor Ferreira ^[1] ; Albino, Amanda Helen ^[1] ; Alarcon Arias, Simone Costa ^[1] ; Volpini, Rildo Aparecido ^[1] ; Avancini Costa Malheiros, Denise Maria ^[1] ; Saraiva Camara, Niels Olsen ^{[2, 1]} ; Zatz, Roberto ^[1] ; Fujihara, Clarke Kazue ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Med, Dept Clin Med, Renal Div, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Biomed Sci, Lab Transplantat Immunobiol, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY; v. 317, n. 4, p. F1058-F1067, OCT 2019.
• Citações Web of Science: 0

Resumo

Nitric oxide inhibition with N-omega-nitro-L-arginine methyl ester (L-NAME), along with salt overload, leads to hypertension, albuminuria, glomerulosclerosis, glomerular ischemia, and interstitial fibrosis, characterizing a chronic kidney disease (CKD) model. Previous findings of this laboratory and elsewhere have suggested that activation of at least two pathways of innate immunity, Toll-like receptor 4 (TLR4)/NF-kappa B and nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3 (NLRP3) inflammasome/IL-1 beta, occurs in several experimental models of CKD and that progression of renal injury can be slowed with inhibition of these pathways. In the present study, we investigated whether activation of innate immunity, through either the TLR4/NF-kappa B or NLRP3/IL-1 beta pathway, is involved in the pathogenesis of renal injury in chronic nitric oxide inhibition with the salt-overload model. Adult male Munich-Wistar rats that received L-NAME in drinking water with salt overload (HS + N group) were treated with allopurinol (ALLO) as an NLRP3 inhibitor (HS + N + ALLO group) or pyrrolidine dithiocarbamate (PDTC) as an NF-kappa B inhibitor (HS + N + PDTC group). After 4 wk, HS + N rats developed hypertension, albuminuria, and renal injury along with renal inflammation, oxidative stress, and activation of both the NLRP3/IL-1 beta and TLR4/NF-kappa B pathways. ALLO lowered renal uric acid and inhibited the NLRP3 pathway. These effects were associated with amelioration of hypertension, albuminuria, and interstitial inflammation/fibrosis but not glomerular injury. PDTC inhibited the renal NF-kappa B system and lowered the number of interstitial cells staining positively for NLRP3. PDTC also reduced renal xanthine oxidase activity and uric acid. Overall, PDTC promoted a more efficient anti-inflammatory and nephroprotective effect than ALLO. The NLRP3/IL-1 beta and TLR4/NF-kappa B pathways act in parallel to promote renal injury/inflammation and must be simultaneously inhibited for best nephroprotection. (AU)

• Processo FAPESP: 15/25368-6 - Papel do sistema NFkB e da via do inflamassoma NLRP3 no modelo de inibição crônica de óxido nítrico
• Beneficiário: Fernanda Florencia Fregnan Zambom
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 12/10926-5 - Patogênese e terapêutica da doença renal crônica: papel da imunidade inata na lesão de glomérulos, túbulos e interstício
• Beneficiário: Roberto Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Temático