DENISE MARIA AVANCINI COSTA MALHEIROS
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Patologia, Faculdade de Medicina - Docente
LIM/16 - Laboratório de Fisiopatologia Renal, Hospital das Clínicas, Faculdade de Medicina
LIM/16 - Laboratório de Fisiopatologia Renal, Hospital das Clínicas, Faculdade de Medicina
11 resultados
Resultados de Busca
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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.
- Effects of losartan, in monotherapy or in association with hydrochlorothiazide, in chronic nephropathy resulting from losartan treatment during lactation(2011) FANELLI, C.; FERNANDES, B. H. V.; MACHADO, F. G.; OKABE, C.; MALHEIROS, D. M. A. C.; FUJIHARA, C. K.; ZATZ, R.Fanelli C, Fernandes BH, Machado FG, Okabe C, Malheiros DM, Fujihara CK, Zatz R. Effects of losartan, in monotherapy or in association with hydrochlorothiazide, in chronic nephropathy resulting from losartan treatment during lactation. Am J Physiol Renal Physiol 301: F580-F587, 2011. First published June 8, 2011; doi:10.1152/ajprenal.00042.2011.-We recently standardized a model (L(Lact)) of severe chronic kidney disease based on impaired nephrogenesis by suppression of angiotensin II activity during lactation (Machado FG, Poppi EP, Fanelli C, Malheiros DM, Zatz R, Fujihara CK. Am J Physiol Renal Physiol 294: F1345-F1353, 2008). In this new study of the L(Lact) model, we sought to gain further insight into renal injury mechanisms associated with this model and to verify whether the renoprotection obtained with the association of the angiotensin II receptor blocker losartan (L) and hydrochlorothiazide (H), which arrested renal injury in the remnant kidney model, would provide similar renoprotection. Twenty Munich-Wistar dams, each nursing six pups, were divided into control, untreated, and L(Lact) groups, given losartan (L; 250 mg.kg(-1).day(-1)) until weaning. The male LLact offspring remained untreated until 7 mo of age, when renal functional and structural parameters were studied in 17 of them, used as pretreatment control (L(Lact)Pre), and followed no further. The remaining rats were then divided among groups L(Lact) + V, untreated; L(Lact) + L, given L (50 mg.kg(-1).day(-1)) now as a therapy; L(Lact) + H, given H (6 mg.kg(-1).day(-1)); and L(Lact) + LH, given L and H. All parameters were reassessed 3 mo later in these groups and in age-matched controls. At this time, L(Lact) rats exhibited hypertension, severe albuminuria, glomerular damage, marked interstitial expansion/inflammation, enhanced cell proliferation, myofibroblast infiltration, and creatinine retention. L monotherapy normalized albuminuria and prevented hypertension and the progression of renal injury, inflammation, and myofibroblast infiltration. In contrast to the remnant model, the LH combination promoted only slight additional renoprotection, perhaps because of a limited tendency to retain sodium in L(Lact) rats.
- Chronic environmental hypoxia attenuates innate immunity activation and renal injury in two CKD models(2023) ZAMBOM, Fernanda Florencia Fregnan; ALBINO, Amanda Helen; TESSARO, Helena Mendonca; FORESTO-NETO, Orestes; MALHEIROS, Denise Maria Avancini Costa; CAMARA, Niels Olsen Saraiva; ZATZ, RobertoTissue hypoxia has been pointed out as a major pathogenic factor in chronic kidney disease (CKD). However, epidemiological and experimental evidence inconsistent with this notion has been described. We have previously reported that chronic exposure to low ambient Po-2 promoted no renal injury in normal rats and in rats with 5/6 renal ablation (Nx) unexpectedly attenuated renal injury. In the present study, we investigated whether chronic exposure to low ambient Po-2 would also be renoprotective in two additional models of CKD: adenine (ADE) excess and chronic nitric oxide (NO) inhibition. In both models, normobaric ambient hypoxia attenuated the development of renal injury and inflammation. In addition, renal hypoxia limited the activation of NF-?B and NOD-like receptor family pyrin domain containing 3 inflammasome cascades as well as oxidative stress and intrarenal infiltration by angiotensin II-positive cells. Renal activation of hypoxia-inducible factor (HIF)-2a, along with other adaptive mechanisms to hypoxia, may have contributed to these renoprotective effects. The present findings may contribute to unravel the pathogenesis of CKD and to the development of innovative strategies to arrest its progression.
- Pathogenic role of angiotensin II and the NF-kappa B system in a model of malignant hypertensive nephrosclerosis(2019) AVILA, Victor F.; FORESTO-NETO, Orestes; ARIAS, Simone C. A.; FAUSTINO, Viviane D.; MALHEIROS, Denise M. A. C.; CAMARA, Niels O. S.; ZATZ, Roberto; FUJIHARA, Clarice K.We previously reported that rats treated with an NF-kappa B inhibitor, pyrrolidine dithiocarbamate (PDTC), during lactation developed hypertension in adult life, without apparent functional or structural damage to kidneys, providing a new model of essential hypertension. Here, we investigated whether uninephrectomy associated with salt overload would unveil a latent renal dysfunction in this model, aggravating arterial hypertension and promoting renal injury. Male Munich-Wistar rat pups received PDTC from maternal milk (PDTCLact) from 0 to 20 days after birth. Another group received no treatment during lactation. All offspring underwent uninephrectomy (UNx) at 10 weeks of age and then were subdivided into NS, receiving a normal salt (0.5% Na+) diet, PDTCLact + NS, HS, receiving a high-salt diet (2% Na+ chow + 0.5% saline to drink), and PDTCLact + HS. Twelve weeks later, HS rats were moderately hypertensive with mild albuminuria and renal injury. In contrast, severe hypertension, glomerulosclerosis, and cortical collagen deposition were prominent in PDTCLact + HS animals, along with ""onion-skin"" arteriolar lesions, evidence of oxidative stress and intense renal infiltration by macrophages, and lymphocytes and angiotensin II-positive cells, contrasting with low circulating renin. The NF-kappa B pathway was also activated. In a separate set of PDTC Lact -PHS rats, Losartan treatment prevented NF-kappa B activation and strongly attenuated glomerular injury, cortical fibrosis, and renal inflammation. NF-kappa B activity during late nephrogenesis is essential for the kidneys to properly maintain sodium homeostasis in adult life. Paradoxically, this same system contributed to renal injury resembling that caused by malignant hypertension when renal dysfunction caused by its inhibition during lactation was unmasked by uninephrectomy associated with HS.
- Activation of platelet-activating factor receptor exacerbates renal inflammation and promotes fibrosis(2014) CORREA-COSTA, Matheus; ANDRADE-OLIVEIRA, Vinicius; BRAGA, Tarcio T.; CASTOLDI, Angela; AGUIAR, Cristhiane F.; ORIGASSA, Clarice S. T.; RODAS, Andrea C. D.; HIYANE, Meire I.; MALHEIROS, Denise M. A. C.; RIOS, Francisco J. O.; JANCAR, Sonia; CAMARA, Niels O. S.Platelet-activating factor (PAF) is a lipid mediator with important pro-inflammatory effects, being synthesized by several cell types including kidney cells. Although there is evidence of its involvement in acute renal dysfunction, its role in progressive kidney injury is not completely known. In the present study, we investigated the role of PAF receptor (PAFR) in an experimental model of chronic renal disease. Wild-type (WT) and PAFR knockout (KO) mice underwent unilateral ureter obstruction (UUO), and at kill time, urine and kidney tissue was collected. PAFR KO animals compared with WT mice present: (a) less renal dysfunction, evaluated by urine protein/creatinine ratio; (b) less fibrosis evaluated by collagen deposition, type I collagen, Lysyl Oxidase-1 (LOX-1) and transforming growth factor beta (TGF-beta) gene expression, and higher expression of bone morphogenetic protein 7 (BMP-7) (3.3-fold lower TGF-beta/BMP-7 ratio); (c) downregulation of extracellular matrix (ECM) and adhesion molecule-related machinery genes; and (d) lower levels of pro-inflammatory cytokines. These indicate that PAFR engagement by PAF or PAF-like molecules generated during UUO potentiates renal dysfunction and fibrosis and might promote epithelial-to-mesenchymal transition (EMT). Also, early blockade of PAFR after UUO leads to a protective effect, with less fibrosis deposition. In conclusion, PAFR signaling contributes to a pro-inflammatory environment in the model of obstructive nephropathy, favoring the fibrotic process, which lately will generate renal dysfunction and progressive organ failure.
- An association of losartan-hydrochlorothiazide, but not losartan-furosemide, completely arrests progressive injury in the remnant kidney(2016) ARIAS, Simone Costa Alarcon; SOUZA, Renata Alves; MALHEIROS, Denise Maria Avancini Costa; FANELLI, Camilla; FUJIHARA, Clarice Kazue; ZATZ, RobertoWe have previously shown that an association of losartan and hydrochlorothiazide, initiated 1 mo after 5/6 nephrectomy (Nx), reversed hypertension and albuminuria and promoted lasting renoprotection. In this new study, we investigated whether equal or even better protection could be obtained by combining losartan and furosemide. Nx was performed in 58 Munich-Wistar rats. One month later, tail-cuff pressure and albuminuria were markedly elevated. At this time, Nx rats were distributed among the following four groups: untreated Nx rats, Nx rats that received losartan, Nx rats that received losartan + hydrochlorothiazide, and Nx rats that received losartan + furosemide. Seven months later, Nx rats exhibited high mortality, severe hypertension, albuminuria, glomerulosclerosis, and interstitial fibrosis. Losartan treatment limited mortality and attenuated the renal and hemodynamic abnormalities associated with Nx. As previously shown, the losartan + hydrochlorothiazide association normalized tail-cuff pressure and albumin, prevented renal injury, and reduced mortality to zero. The losartan + furosemide treatment failed to reduce tail-cuff pressure or albumin to normal and prevented renal injury less efficiently than the losartan and hydrochlorothiazide regimen. The reasons for the differing efficacies of the losartan + furosemide and losartan + hydrochlorothiazide schemes are unclear and may include beneficial nondiuretic actions of thiazides, such as vasorelaxation and antiproliferative activity. These results refute the established concept that thiazides and thiazide-like diuretics are ineffective at advanced chronic kidney disease stages. Rather, they suggest that, in view of their renoprotective action, these compounds may even be preferable to loop diuretics in the management of hypertension in advanced chronic kidney disease.
- Chronic exposure to hypoxia attenuates renal injury and innate immunity activation in the remnant kidney model(2019) REMPEL, Lisienny Campoli Tono; FAUSTINO, Viviane Dias; FORESTO-NETO, Orestes; FANELLI, Camilla; ARIAS, Simone Costa Alarcon; MOREIRA, Gizely Cristina da Silva; NASCIMENTO, Thalita Fabiana; AVILA, Victor Ferreira; MALHEIROS, Denise Maria Avancini Costa; CAMARA, Niels Olsen Saraiva; FUJIHARA, Clarice Kazue; ZATZ, RobertoHypoxia is thought to influence the pathogenesis of chronic kidney disease, but direct evidence that prolonged exposure to tissue hypoxia initiates or aggravates chronic kidney disease is lacking. We tested this hypothesis by chronically exposing normal rats and rats with 5/6 nephrectomy (Nx) to hypoxia. In addition, we investigated whether such effect of hypoxia would involve activation of innate immunity. Adult male Munich-Wistar rats underwent Nx (n = 54) or sham surgery (sham; n = 52). Twenty-six sham rats and 26 Nx rats remained in normoxia, whereas 26 sham rats and 28 Nx rats were kept in a normobaric hypoxia chamber (12% O-2) for 8 wk. Hypoxia was confirmed by immunohistochemistry for pimonidazole. Hypoxia was confined to the medullary area in sham + normoxia rats and spread to the cortical area in sham + hypoxia rats, without changing the peritubular capillary density. Exposure to hypoxia promoted no renal injury or elevation of the content of IL-1 beta or Toll-like receptor 4 in sham rats. In Nx, hypoxia also extended to the cortical area without ameliorating the peritubular capillary rarefaction but, unexpectedly, attenuated hypertension, inflammation, innate immunity activation, renal injury, and oxidative stress. The present study, in disagreement with current concepts. shows evidence that hypoxia exerts a renoprotective effect in the Nx model instead of acting as a factor of renal injury. The mechanisms for this unexpected beneficial effect are unclear and may involve NF-kappa B inhibition, amelioration of oxidative stress, and limitation of angiotensin II production by the renal tissue.
- NF-kappa B activation mediates crystal translocation and interstitial inflammation in adenine overload nephropathy(2013) OKABE, Cristiene; BORGES, Raquel Lerner; ALMEIDA, Danilo Candido de; FANELLI, Camilla; BARLETTE, Grasiela Pedreira; MACHADO, Flavia Gomes; ARIAS, Simone Costa Alarcon; MALHEIROS, Denise Maria Avancini Costa; CAMARA, Niels Olsen Saraiva; ZATZ, Roberto; FUJIHARA, Clarice KazueAdenine overload promotes intratubular crystal precipitation and interstitial nephritis. We showed recently that these abnormalities are strongly attenuated in mice knockout for Toll-like receptors-2, -4, MyD88, ASC, or caspase-1. We now investigated whether NF-kappa B activation also plays a pathogenic role in this model. Adult male Munich-Wistar rats were distributed among three groups: C (n = 17), receiving standard chow; ADE (n = 17), given adenine in the chow at 0.7% for 1 wk and 0.5% for 2 wk; and ADE + pyrrolidine dithiocarbamate (PDTC; n = 14), receiving adenine as above and the NF-kappa B inhibitor PDTC (120 mg.kg(-1).day(-1) in the drinking water). After 3 wk, widespread crystal deposition was seen in tubular lumina and in the renal interstitium, along with granuloma formation, collagen accumulation, intense tubulointerstitial proliferation, and increased interstitial expression of inflammatory mediators. Part of the crystals were segregated from tubular lumina by a newly formed cell layer and, at more advanced stages, appeared to be extruded to the interstitium. p65 nuclear translocation and IKK-alpha increased abundance indicated activation of the NF-kappa B system. PDTC treatment prevented p65 migration and normalized IKK-alpha, limited crystal shift to the interstitium, and strongly attenuated interstitial fibrosis/inflammation. These findings indicate that the complex inflammatory phenomena associated with this model depend, at least in part, on NF-kappa B activation, and suggest that the NF-kappa B system may become a therapeutic target in the treatment of chronic kidney disease.
- 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.
- Metformin arrests the progression of established kidney disease in the subtotal nephrectomy model of chronic kidney disease(2020) BORGES, Cynthia M.; FUJIHARA, Clarice Kazue; MALHEIROS, Denise M. A. C.; AVILA, Victor Ferreira de; FORMIGARI, Guilherme Pedrom; FARIA, Jose B. Lopes deMetformin. an AMP-activated protein kinase (AMPK) activator, has been shown in previous studies to reduce kidney fibrosis in different models of experimental chronic kidney disease (CKD). However, in all of these studies. the administration of metformin was initiated before the establishment of renal disease, which is a condition that does not typically occur in clinical settings. The aim of the present study was to investigate whether the administration of metformin could arrest the progression of established renal disease in a well-recognized model of CKD, the subtotal kidney nephrectomy (Nx) model. Adult male Munich-Wistar rats underwent either Nx or sham operations. After the surgery (30 days), Nx rats that had systolic blood pressures of >170 mmHg and albuminuria levels of >40 mg/24 h were randomized to a no-treatment condition or to a treatment condition with metformin (300 mg.kg(-1).day(-1)) for a period of either 60 or 120 days. After 60 days of treatment. we did not observe any differences in kidney disease parameters between Nx metformin-treated and untreated rats. However, after 120 days, Nx rats that had been treated with metformin displayed significant reductions in albuminuria levels and in markers of renal fibrosis. These effects were independent of any other effects on blood pressure or glycemia. In addition, treatment with metformin was also able to activate kidney AMPK and therefore improve mitochondrial biogenesis. It was concluded that metformin can arrest the progression of established kidney disease in the Nx model, likely via the activation of AMPK.