AMANDA HELEN ALBINO
Projetos de Pesquisa
Unidades Organizacionais
LIM/16 - Laboratório de Fisiopatologia Renal, Hospital das Clínicas, Faculdade de Medicina
2 resultados
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- Pathogenic role of innate immunity in a model of chronic NO inhibition associated with salt overload(2019) ZAMBOM, Fernanda Florencia Fregnan; OLIVEIRA, Karin Carneiro; FORESTO-NETO, Orestes; FAUSTINO, Viviane Dias; AVILA, Victor Ferreira; ALBINO, Amanda Helen; ARIAS, Simone Costa Alarcon; VOLPINI, Rildo Aparecido; MALHEIROS, Denise Maria Avancini Costa; CAMARA, Niels Olsen Saraiva; ZATZ, Roberto; FUJIHARA, Clarke KazueNitric 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.
- NF-kappa B blockade during short-term L-NAME and salt overload strongly attenuates the late development of chronic kidney disease(2020) OLIVEIRA, Karin Carneiro; ZAMBOM, Fernanda Florencia Fregnan; ALBINO, Amanda Helen; ARIAS, Simone Costa Alarcon; AVILA, Victor Ferreira; FAUSTINO, Viviane Dias; MALHEIROS, Denise Maria Avancini Costa; CAMARA, Niels Olsen Saraiva; FUJIHARA, Clarice Kazue; ZATZ, RobertoNitric oxide synthase inhibition by N-omega-nitro-L-arginine methyl ester (L-NAME) plus a high-salt diet (HS) is a model of chronic kidney disease (CKD) characterized by marked hypertension and renal injury. With cessation of treatment, most of these changes subside, but progressive renal injury develops, associated with persistent low-grade renal inflammation. We investigated whether innate immunity. and in particular the NF-kappa B system, is involved in this process. Male Munich-Wistar rats received HS + L-NAME (32 mg.kg(-1).day(-1)), whereas control rats received HS only. Treatment was ceased after week 4 when 30 rats were studied. Additional rats were studied at week 8 (n = 30) and week 28 (n = 30). As expected, HS + L-NAME promoted severe hypertension, albuminuria, and renal injury after 4 wk of treatment, whereas innate immunity activation was evident. After discontinuation of treatments, partial regression of renal injury and inflammation occurred, along with persistence of innate immunity activation at week 8. At week 28, glomerular injury worsened, while renal inflammation persisted and renal innate immunity remained activated. Temporary administration of the NF-kappa B inhibitor pyrrolidine dithiocarbamate, in concomitancy with the early 4-wk HS + L-NAME treatment, prevented the development of late renal injury and inflammation, an effect that lasted until the end of the study. Early activation of innate immunity may be crucial to the initiation of renal injury in the HS + L-NAME model and to the autonomous progression of chronic nephropathy even after cessation of the original insult. This behavior may be common to other conditions leading to CKD.