Fernanda Zambom - Academia.edu (original) (raw)

Papers by Fernanda Zambom

Research paper thumbnail of Correction to: Hypoxia enhances ILC3 responses through HIF-1α-dependent mechanism

Mucosal Immunology, Jul 1, 2021

Research paper thumbnail of Hypoxia enhances ILC3 responses through HIF-1α-dependent mechanism

Mucosal Immunology, 2021

Group 3 innate lymphoid cells (ILC3) have a prominent role in the maintenance of intestine mucosa... more Group 3 innate lymphoid cells (ILC3) have a prominent role in the maintenance of intestine mucosa homeostasis. The hypoxia-inducible factor (HIF) is an important modulator of immune cell activation and a key mechanism for cellular adaptation to oxygen deprivation. However, its role on ILC3 is not well known. In this study, we investigated how a hypoxic environment modulates ILC3 response and the subsequent participation of HIF-1 signaling in this process. We found increased proliferation and activation of intestinal ILC3 at low oxygen levels, a response that was phenocopied when HIF-1α was chemically stabilized and was reversed when HIF-1 was blocked. The increased activation of ILC3 relied on a HIF-1α-dependent transcriptional program, but not on mTOR-signaling or a switch to glycolysis. HIF-1α deficiency in RORyt compartment resulted in impaired IL-17 and IL-22 production by ILC3 in vivo, which reflected in a lower expression of their target genes in the intestinal epithelium and ...

Research paper thumbnail of Chronic environmental hypoxia attenuates innate immunity activation and renal injury in two CKD models

American Journal of Physiology-Renal Physiology

Hypoxia is regarded as a major pathogenic factor in chronic kidney disease (CKD). In disagreement... more Hypoxia is regarded as a major pathogenic factor in chronic kidney disease (CKD). In disagreement with this view, we show here that sustained exposure to low ambient Po2 lessened kidney injury and inflammation in two CKD models: adenine (ADE) excess and chronic nitric oxide (NO) inhibition. Together with our previous findings in the remnant kidney, these observations indicate that local changes elicited by hypoxia may exert renoprotection in CKD, raising the prospect of novel therapeutic strategies for this disease.

Research paper thumbnail of Efeito da hipóxia na patogênese da lesão renal em dois modelos experimentais de doença renal crônica: agravamento ou proteção?

Research paper thumbnail of SUN-211 Tissue Hypoxia Attenuated Rather Than Aggravated Renal Injury and Inflammation in Rats with Chronic No Inhibition

Kidney International Reports, 2019

Research paper thumbnail of AT1-RECEPTOR Blockade After Short-Term L-Name and Salt Overload Prevents Innate Immunity Activation and Strongly Attenuates the Late Development of Chronic Kidney Disease

Journal of Hypertension, 2019

Objective:We showed previously (AJPRenal 2006) that short-term NO inhibition by L-NAME (N) and sa... more Objective:We showed previously (AJPRenal 2006) that short-term NO inhibition by L-NAME (N) and salt overload (HS) promotes severe hypertension and renal injury that regress after treatment is ceased, but progress slowly to chronic kidney disease (CKD) thereafter. Here we investigated whether angiote

Research paper thumbnail of AT1-RECEPTOR Blockade After Short-Term L-Name and Salt Overload Prevents Innate Immunity Activation and Strongly Attenuates the Late Development of Chronic Kidney Disease

Journal of Hypertension, 2019

Objective:We showed previously (AJPRenal 2006) that short-term NO inhibition by L-NAME (N) and sa... more Objective:We showed previously (AJPRenal 2006) that short-term NO inhibition by L-NAME (N) and salt overload (HS) promotes severe hypertension and renal injury that regress after treatment is ceased, but progress slowly to chronic kidney disease (CKD) thereafter. Here we investigated whether angiote

Research paper thumbnail of Simultaneous activation of innate and adaptive immunity participates in the development of renal injury in a model of heavy proteinuria

Bioscience reports, Jan 18, 2018

Protein overload of proximal tubular cells can promote interstitial injury by unclear mechanisms ... more Protein overload of proximal tubular cells can promote interstitial injury by unclear mechanisms that may involve activation of innate immunity. We investigated whether prolonged exposure of tubular cells to high protein concentrations stimulates innate immunity, triggering progressive interstitial inflammation and renal injury, and whether specific inhibition of innate or adaptive immunity would provide renoprotection in an established model of massive proteinuria, adriamycin (ADR) nephropathy. Adult male Munich-Wistar rats received a single dose of ADR (5 mg/kg iv), being followed for 2, 4 or 20 weeks. Massive albuminuria was associated with early activation of both the NF-κB and NLRP3 innate immunity pathways, whose intensity correlated strongly with the density of lymphocyte infiltration. In addition, ADR rats exhibited clear signs of renal oxidative stress. Twenty weeks after ADR administration, marked interstitial fibrosis, glomerulosclerosis and renal functional loss were obs...

Research paper thumbnail of NLRP3 inflammasome inhibition ameliorates tubulointerstitial injury in the remnant kidney model

Laboratory investigation; a journal of technical methods and pathology, Jan 6, 2018

Recent studies suggest that NLRP3 inflammasome activation is involved in the pathogenesis of chro... more Recent studies suggest that NLRP3 inflammasome activation is involved in the pathogenesis of chronic kidney disease (CKD). Allopurinol (ALLO) inhibits xanthine oxidase (XOD) activity, and, consequently, reduces the production of uric acid (UA) and reactive oxygen species (ROS), both of which can activate the NLRP3 pathway. Thus, ALLO can contribute to slow the progression of CKD. We investigated whether inhibition of XOD by ALLO reduces NLRP3 activation and renal injury in the 5/6 renal ablation (Nx) model. Adult male Munich-Wistar rats underwent Nx and were subdivided into the following two groups: Nx, receiving vehicle only, and Nx + ALLO, Nx rats given ALLO, 36 mg/Kg/day in drinking water. Rats undergoing sham operation were studied as controls (C). Sixty days after surgery, Nx rats exhibited marked albuminuria, creatinine retention, and hypertension, as well as glomerulosclerosis, tubular injury, and cortical interstitial expansion/inflammation/fibrosis. Such changes were accomp...

Research paper thumbnail of Inhibition of both the TLR4/NF-kB and NLRP3 inflammasome pathways prevents CKD in a model of chronic NO inhibition associated with salt overload

A inibição crônica do óxido nítrico com Nw-nitroargininemethylester (L-NAME), associado à sobreca... more A inibição crônica do óxido nítrico com Nw-nitroargininemethylester (L-NAME), associado à sobrecarga de sal, leva a hipertensão grave, albuminúria, glomeruloesclerose, isquemia glomerular e fibrose intersticial, caracterizando um modelo de doença renal crônica (DRC). Achados anteriores deste laboratório e de outros sugerem que a ativação de pelo menos duas vias da imunidade inata, TLR4/NF-kB e NLRP3/IL-1beta, ocorre em vários modelos experimentais de DRC e que a progressão da lesão renal pode ser atenuada com a inibição destas vias. No presente estudo, investigamos se a ativação da imunidade inata, através da via TLR4/NF-kB ou NLRP3/IL-1beta, está envolvida na patogênese da lesão renal em outro modelo de DRC, o de inibição crônica do NO com sobrecarga de sal. Ratos Munich-Wistar machos adultos receberam sobrecarga de sal (2% Na+ na dieta e 0,5% Na+ na água do bebedouro) e L-NAME (32 mg/Kg/dia) dissolvido na salina do bebedouro (Grupo HS+N) ou tratados com alopurinol (Alo, 36 mg/Kg/d...

Research paper thumbnail of SUN-311 NF-Kappa B Activation Promotes Glomerular Injury and Inflammation in Long-Term Experimental Diabetic Kidney Disease

Kidney International Reports, Jul 1, 2019

0.619). In binary logistic regression model, the combination of megalin positive >1mm EVs(with ev... more 0.619). In binary logistic regression model, the combination of megalin positive >1mm EVs(with every 10-fold increase: OR=3.74, 95%CI 1.12-12.53; p=0.033), podocin and nephrin positive MVs (with every 10-fold increase: OR=4.03, 95%CI 1.63-9.95; p=0.003), and Annexin-V positive MVs (with every 10-fold increase: OR=0.30, 95%CI 0.10-0.85; p=0.024) best discriminated DN patients from proteinuric controls with the specificity of 89.29% and sensitivity of 67.35%. Detection of EVs Conclusions: Urinary EVs might be an intriguing noninvasive approach to discriminate DN from non-DN proteinuric glomerulopathy, which could be particularly meaningful in differential diangosis of diabetic patients with overt proteinuria, whereas additional validation is needed. Further researches are also needed to unveil mechanisms underlying the changes of urinary EVs in DN.

Research paper thumbnail of Renal Inflammation and Innate Immune Activation Underlie the Transition From Gentamicin-Induced Acute Kidney Injury to Renal Fibrosis

Frontiers in Physiology

Subjects recovering from acute kidney injury (AKI) are at risk of developing chronic kidney disea... more Subjects recovering from acute kidney injury (AKI) are at risk of developing chronic kidney disease (CKD). The mechanisms underlying this transition are unclear and may involve sustained activation of renal innate immunity, with resulting renal inflammation and fibrosis. We investigated whether the NF-κB system and/or the NLRP3 inflammasome pathway remain activated after the resolution of AKI induced by gentamicin (GT) treatment, thus favoring the development of CKD. Male Munich-Wistar rats received daily subcutaneous injections of GT, 80 mg/kg, for 9 days. Control rats received vehicle only (NC). Rats were studied at 1, 30, and 180 days after GT treatment was ceased. On Day 1, glomerular ischemia (ISCH), tubular necrosis, albuminuria, creatinine retention, and tubular dysfunction were noted, in association with prominent renal infiltration by macrophages and myofibroblasts, along with increased renal abundance of TLR4, IL-6, and IL1β. Regression of functional and structural changes...

Research paper thumbnail of A inibição das vias TLR4/NF-kB e do NLRP3/IL-1beta previne a DRC em um modelo de inibição crônica de NO associado à  sobrecarga de sal

À minha orientadora Dra Clarice Kazue Fujihara, que esteve comigo desde o início desse trabalho, ... more À minha orientadora Dra Clarice Kazue Fujihara, que esteve comigo desde o início desse trabalho, me ensinou e me fez crescer como pessoa e profissional. Sem ela nada disto teria acontecido. Sempre com entusiasmo e otimismo em relação ao meu trabalho e a mim, como sua aluna. Obrigada pela confiança. Meus mais sinceros agradecimentos. Ao Prof Dr Roberto Zatz, que me recebeu muito bem, sempre com ótimas piadas e otimismo em relação à vida e à busca pelo saber cientifico. Você é um exemplo, de simplicidade e grandiosidade. Ao Prof Dr Niels Olsen Saraiva Câmara pela parceria e contribuição na construção desse trabalho, com sugestões brilhantes, que me despertou mais vontade de aprender e buscar crescer profissionalmente. Um exemplo de pessoa, professor e pesquisador. À Dra Denise Malheiros pela enorme colaboração. Agradeço imensamente pela paciência em analisar as inúmeras lâminas e pelas preciosas discussões sobre os resultados. Aos meus amigos do LIM,

Research paper thumbnail of NF-κB System Is Chronically Activated and Promotes Glomerular Injury in Experimental Type 1 Diabetic Kidney Disease

Frontiers in Physiology

High glucose concentration can activate TLR4 and NF-κB, triggering the production of proinflammat... more High glucose concentration can activate TLR4 and NF-κB, triggering the production of proinflammatory mediators. We investigated whether the NF-κB pathway is involved in the pathogenesis and progression of experimental diabetic kidney disease (DKD) in a model of long-term type 1 diabetes mellitus (DM). Adult male Munich-Wistar rats underwent DM by a single streptozotocin injection, and were kept moderately hyperglycemic by daily insulin injections. After 12 months, two subgroups-progressors and non-progressors-could be formed based on the degree of glomerulosclerosis. Only progressors exhibited renal TLR4, NF-κB and IL-6 activation. This scenario was already present in rats with short-term DM (2 months), at a time when no overt glomerulosclerosis can be detected. Chronic treatment with the NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), prevented activation of renal TLR4, NF-κB or IL-6, without interfering with blood glucose. PDTC prevented the development of glomerular injury/inflammation and oxidative stress in DM rats. In addition, the NF-κB p65 component was detected in sclerotic glomeruli and inflamed interstitial areas in biopsy material from patients with type 1 DM. These observations indicate that the renal NF-κB pathway plays a key role in the development and progression of experimental DKD, and can become an important therapeutic target in the quest to prevent the progression of human DKD.

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

American Journal of Physiology-Renal Physiology

Nitric oxide inhibition with Nw-nitroarginine-methylester (L-NAME) along with salt overload leads... more Nitric oxide inhibition with Nw-nitroarginine-methylester (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 suggest that activation of at least two pathways of innate immunity, TLR4/NF-κB and NLRP3 inflammasome/IL-1β, 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-κB or NLRP3/IL-1β pathway, is involved in the pathogenesis of renal injury in chronic NO inhibition with salt overload model. Adult male Munich-Wistar rats receiving L-NAME in drinking water and salt overload (Group HS+N) were treated with Allopurinol (ALLO), as an NLRP3 inhibitor (Group HS+N+ALLO), or Pyrrolidine Dithiocarbamate (PDTC) a NF-κB inhib...

Research paper thumbnail of NF-κB blockade during short-term l-NAME and salt overload strongly attenuates the late development of chronic kidney disease

American Journal of Physiology-Renal Physiology

Nitric oxide synthase inhibition by Nω-nitro-l-arginine methyl ester (l-NAME) plus a high-salt di... more Nitric oxide synthase inhibition by Nω-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-κB 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 immun...

Research paper thumbnail of Correction to: Hypoxia enhances ILC3 responses through HIF-1α-dependent mechanism

Mucosal Immunology, Jul 1, 2021

Research paper thumbnail of Hypoxia enhances ILC3 responses through HIF-1α-dependent mechanism

Mucosal Immunology, 2021

Group 3 innate lymphoid cells (ILC3) have a prominent role in the maintenance of intestine mucosa... more Group 3 innate lymphoid cells (ILC3) have a prominent role in the maintenance of intestine mucosa homeostasis. The hypoxia-inducible factor (HIF) is an important modulator of immune cell activation and a key mechanism for cellular adaptation to oxygen deprivation. However, its role on ILC3 is not well known. In this study, we investigated how a hypoxic environment modulates ILC3 response and the subsequent participation of HIF-1 signaling in this process. We found increased proliferation and activation of intestinal ILC3 at low oxygen levels, a response that was phenocopied when HIF-1α was chemically stabilized and was reversed when HIF-1 was blocked. The increased activation of ILC3 relied on a HIF-1α-dependent transcriptional program, but not on mTOR-signaling or a switch to glycolysis. HIF-1α deficiency in RORyt compartment resulted in impaired IL-17 and IL-22 production by ILC3 in vivo, which reflected in a lower expression of their target genes in the intestinal epithelium and ...

Research paper thumbnail of Chronic environmental hypoxia attenuates innate immunity activation and renal injury in two CKD models

American Journal of Physiology-Renal Physiology

Hypoxia is regarded as a major pathogenic factor in chronic kidney disease (CKD). In disagreement... more Hypoxia is regarded as a major pathogenic factor in chronic kidney disease (CKD). In disagreement with this view, we show here that sustained exposure to low ambient Po2 lessened kidney injury and inflammation in two CKD models: adenine (ADE) excess and chronic nitric oxide (NO) inhibition. Together with our previous findings in the remnant kidney, these observations indicate that local changes elicited by hypoxia may exert renoprotection in CKD, raising the prospect of novel therapeutic strategies for this disease.

Research paper thumbnail of Efeito da hipóxia na patogênese da lesão renal em dois modelos experimentais de doença renal crônica: agravamento ou proteção?

Research paper thumbnail of SUN-211 Tissue Hypoxia Attenuated Rather Than Aggravated Renal Injury and Inflammation in Rats with Chronic No Inhibition

Kidney International Reports, 2019

Research paper thumbnail of AT1-RECEPTOR Blockade After Short-Term L-Name and Salt Overload Prevents Innate Immunity Activation and Strongly Attenuates the Late Development of Chronic Kidney Disease

Journal of Hypertension, 2019

Objective:We showed previously (AJPRenal 2006) that short-term NO inhibition by L-NAME (N) and sa... more Objective:We showed previously (AJPRenal 2006) that short-term NO inhibition by L-NAME (N) and salt overload (HS) promotes severe hypertension and renal injury that regress after treatment is ceased, but progress slowly to chronic kidney disease (CKD) thereafter. Here we investigated whether angiote

Research paper thumbnail of AT1-RECEPTOR Blockade After Short-Term L-Name and Salt Overload Prevents Innate Immunity Activation and Strongly Attenuates the Late Development of Chronic Kidney Disease

Journal of Hypertension, 2019

Objective:We showed previously (AJPRenal 2006) that short-term NO inhibition by L-NAME (N) and sa... more Objective:We showed previously (AJPRenal 2006) that short-term NO inhibition by L-NAME (N) and salt overload (HS) promotes severe hypertension and renal injury that regress after treatment is ceased, but progress slowly to chronic kidney disease (CKD) thereafter. Here we investigated whether angiote

Research paper thumbnail of Simultaneous activation of innate and adaptive immunity participates in the development of renal injury in a model of heavy proteinuria

Bioscience reports, Jan 18, 2018

Protein overload of proximal tubular cells can promote interstitial injury by unclear mechanisms ... more Protein overload of proximal tubular cells can promote interstitial injury by unclear mechanisms that may involve activation of innate immunity. We investigated whether prolonged exposure of tubular cells to high protein concentrations stimulates innate immunity, triggering progressive interstitial inflammation and renal injury, and whether specific inhibition of innate or adaptive immunity would provide renoprotection in an established model of massive proteinuria, adriamycin (ADR) nephropathy. Adult male Munich-Wistar rats received a single dose of ADR (5 mg/kg iv), being followed for 2, 4 or 20 weeks. Massive albuminuria was associated with early activation of both the NF-κB and NLRP3 innate immunity pathways, whose intensity correlated strongly with the density of lymphocyte infiltration. In addition, ADR rats exhibited clear signs of renal oxidative stress. Twenty weeks after ADR administration, marked interstitial fibrosis, glomerulosclerosis and renal functional loss were obs...

Research paper thumbnail of NLRP3 inflammasome inhibition ameliorates tubulointerstitial injury in the remnant kidney model

Laboratory investigation; a journal of technical methods and pathology, Jan 6, 2018

Recent studies suggest that NLRP3 inflammasome activation is involved in the pathogenesis of chro... more Recent studies suggest that NLRP3 inflammasome activation is involved in the pathogenesis of chronic kidney disease (CKD). Allopurinol (ALLO) inhibits xanthine oxidase (XOD) activity, and, consequently, reduces the production of uric acid (UA) and reactive oxygen species (ROS), both of which can activate the NLRP3 pathway. Thus, ALLO can contribute to slow the progression of CKD. We investigated whether inhibition of XOD by ALLO reduces NLRP3 activation and renal injury in the 5/6 renal ablation (Nx) model. Adult male Munich-Wistar rats underwent Nx and were subdivided into the following two groups: Nx, receiving vehicle only, and Nx + ALLO, Nx rats given ALLO, 36 mg/Kg/day in drinking water. Rats undergoing sham operation were studied as controls (C). Sixty days after surgery, Nx rats exhibited marked albuminuria, creatinine retention, and hypertension, as well as glomerulosclerosis, tubular injury, and cortical interstitial expansion/inflammation/fibrosis. Such changes were accomp...

Research paper thumbnail of Inhibition of both the TLR4/NF-kB and NLRP3 inflammasome pathways prevents CKD in a model of chronic NO inhibition associated with salt overload

A inibição crônica do óxido nítrico com Nw-nitroargininemethylester (L-NAME), associado à sobreca... more A inibição crônica do óxido nítrico com Nw-nitroargininemethylester (L-NAME), associado à sobrecarga de sal, leva a hipertensão grave, albuminúria, glomeruloesclerose, isquemia glomerular e fibrose intersticial, caracterizando um modelo de doença renal crônica (DRC). Achados anteriores deste laboratório e de outros sugerem que a ativação de pelo menos duas vias da imunidade inata, TLR4/NF-kB e NLRP3/IL-1beta, ocorre em vários modelos experimentais de DRC e que a progressão da lesão renal pode ser atenuada com a inibição destas vias. No presente estudo, investigamos se a ativação da imunidade inata, através da via TLR4/NF-kB ou NLRP3/IL-1beta, está envolvida na patogênese da lesão renal em outro modelo de DRC, o de inibição crônica do NO com sobrecarga de sal. Ratos Munich-Wistar machos adultos receberam sobrecarga de sal (2% Na+ na dieta e 0,5% Na+ na água do bebedouro) e L-NAME (32 mg/Kg/dia) dissolvido na salina do bebedouro (Grupo HS+N) ou tratados com alopurinol (Alo, 36 mg/Kg/d...

Research paper thumbnail of SUN-311 NF-Kappa B Activation Promotes Glomerular Injury and Inflammation in Long-Term Experimental Diabetic Kidney Disease

Kidney International Reports, Jul 1, 2019

0.619). In binary logistic regression model, the combination of megalin positive >1mm EVs(with ev... more 0.619). In binary logistic regression model, the combination of megalin positive >1mm EVs(with every 10-fold increase: OR=3.74, 95%CI 1.12-12.53; p=0.033), podocin and nephrin positive MVs (with every 10-fold increase: OR=4.03, 95%CI 1.63-9.95; p=0.003), and Annexin-V positive MVs (with every 10-fold increase: OR=0.30, 95%CI 0.10-0.85; p=0.024) best discriminated DN patients from proteinuric controls with the specificity of 89.29% and sensitivity of 67.35%. Detection of EVs Conclusions: Urinary EVs might be an intriguing noninvasive approach to discriminate DN from non-DN proteinuric glomerulopathy, which could be particularly meaningful in differential diangosis of diabetic patients with overt proteinuria, whereas additional validation is needed. Further researches are also needed to unveil mechanisms underlying the changes of urinary EVs in DN.

Research paper thumbnail of Renal Inflammation and Innate Immune Activation Underlie the Transition From Gentamicin-Induced Acute Kidney Injury to Renal Fibrosis

Frontiers in Physiology

Subjects recovering from acute kidney injury (AKI) are at risk of developing chronic kidney disea... more Subjects recovering from acute kidney injury (AKI) are at risk of developing chronic kidney disease (CKD). The mechanisms underlying this transition are unclear and may involve sustained activation of renal innate immunity, with resulting renal inflammation and fibrosis. We investigated whether the NF-κB system and/or the NLRP3 inflammasome pathway remain activated after the resolution of AKI induced by gentamicin (GT) treatment, thus favoring the development of CKD. Male Munich-Wistar rats received daily subcutaneous injections of GT, 80 mg/kg, for 9 days. Control rats received vehicle only (NC). Rats were studied at 1, 30, and 180 days after GT treatment was ceased. On Day 1, glomerular ischemia (ISCH), tubular necrosis, albuminuria, creatinine retention, and tubular dysfunction were noted, in association with prominent renal infiltration by macrophages and myofibroblasts, along with increased renal abundance of TLR4, IL-6, and IL1β. Regression of functional and structural changes...

Research paper thumbnail of A inibição das vias TLR4/NF-kB e do NLRP3/IL-1beta previne a DRC em um modelo de inibição crônica de NO associado à  sobrecarga de sal

À minha orientadora Dra Clarice Kazue Fujihara, que esteve comigo desde o início desse trabalho, ... more À minha orientadora Dra Clarice Kazue Fujihara, que esteve comigo desde o início desse trabalho, me ensinou e me fez crescer como pessoa e profissional. Sem ela nada disto teria acontecido. Sempre com entusiasmo e otimismo em relação ao meu trabalho e a mim, como sua aluna. Obrigada pela confiança. Meus mais sinceros agradecimentos. Ao Prof Dr Roberto Zatz, que me recebeu muito bem, sempre com ótimas piadas e otimismo em relação à vida e à busca pelo saber cientifico. Você é um exemplo, de simplicidade e grandiosidade. Ao Prof Dr Niels Olsen Saraiva Câmara pela parceria e contribuição na construção desse trabalho, com sugestões brilhantes, que me despertou mais vontade de aprender e buscar crescer profissionalmente. Um exemplo de pessoa, professor e pesquisador. À Dra Denise Malheiros pela enorme colaboração. Agradeço imensamente pela paciência em analisar as inúmeras lâminas e pelas preciosas discussões sobre os resultados. Aos meus amigos do LIM,

Research paper thumbnail of NF-κB System Is Chronically Activated and Promotes Glomerular Injury in Experimental Type 1 Diabetic Kidney Disease

Frontiers in Physiology

High glucose concentration can activate TLR4 and NF-κB, triggering the production of proinflammat... more High glucose concentration can activate TLR4 and NF-κB, triggering the production of proinflammatory mediators. We investigated whether the NF-κB pathway is involved in the pathogenesis and progression of experimental diabetic kidney disease (DKD) in a model of long-term type 1 diabetes mellitus (DM). Adult male Munich-Wistar rats underwent DM by a single streptozotocin injection, and were kept moderately hyperglycemic by daily insulin injections. After 12 months, two subgroups-progressors and non-progressors-could be formed based on the degree of glomerulosclerosis. Only progressors exhibited renal TLR4, NF-κB and IL-6 activation. This scenario was already present in rats with short-term DM (2 months), at a time when no overt glomerulosclerosis can be detected. Chronic treatment with the NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), prevented activation of renal TLR4, NF-κB or IL-6, without interfering with blood glucose. PDTC prevented the development of glomerular injury/inflammation and oxidative stress in DM rats. In addition, the NF-κB p65 component was detected in sclerotic glomeruli and inflamed interstitial areas in biopsy material from patients with type 1 DM. These observations indicate that the renal NF-κB pathway plays a key role in the development and progression of experimental DKD, and can become an important therapeutic target in the quest to prevent the progression of human DKD.

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

American Journal of Physiology-Renal Physiology

Nitric oxide inhibition with Nw-nitroarginine-methylester (L-NAME) along with salt overload leads... more Nitric oxide inhibition with Nw-nitroarginine-methylester (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 suggest that activation of at least two pathways of innate immunity, TLR4/NF-κB and NLRP3 inflammasome/IL-1β, 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-κB or NLRP3/IL-1β pathway, is involved in the pathogenesis of renal injury in chronic NO inhibition with salt overload model. Adult male Munich-Wistar rats receiving L-NAME in drinking water and salt overload (Group HS+N) were treated with Allopurinol (ALLO), as an NLRP3 inhibitor (Group HS+N+ALLO), or Pyrrolidine Dithiocarbamate (PDTC) a NF-κB inhib...

Research paper thumbnail of NF-κB blockade during short-term l-NAME and salt overload strongly attenuates the late development of chronic kidney disease

American Journal of Physiology-Renal Physiology

Nitric oxide synthase inhibition by Nω-nitro-l-arginine methyl ester (l-NAME) plus a high-salt di... more Nitric oxide synthase inhibition by Nω-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-κB 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 immun...