ROBERTO ZATZ
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina - Docente
LIM/16 - Laboratório de Fisiopatologia Renal, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/16 - Laboratório de Fisiopatologia Renal, Hospital das Clínicas, Faculdade de Medicina - Líder
6 resultados
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- Fluid Redistribution in Sleep Apnea: Therapeutic Implications in Edematous States(2018) SILVA, Bruno Caldin da; KASAI, Takatoshi; COELHO, Fernando Morgadinho; ZATZ, Roberto; ELIAS, Rosilene M.Sleep apnea (SA), a condition associated with increased cardiovascular risk, has been traditionally associated with obesity and aging. However, in patients with fluid-retaining states, such as congestive heart failure and end-stage renal disease, both prevalence and severity of SA are increased. Recently, fluid shift has been recognized to play an important role in the pathophysiology of SA, since the fluid retained in the legs during the day shifts rostrally while recumbent, leading to edema of upper airways. Such simple physics, observed even in healthy individuals, has great impact in patients with fluid overload. Correction of the excess fluid volume has risen as a potential target therapy to improve SA, by attenuation of nocturnal fluid shift. Such strategy has gained special attention, since the standard treatment for SA, the positive airway pressure, has low compliance rates among its users and has failed to reduce cardiovascular outcomes. This review focuses on the pathophysiology of edema and fluid shift, and summarizes the most relevant findings of studies that investigated the impact of treating volume overload on SA. We aim to expand horizons in the treatment of SA by calling attention to a potentially reversible condition, which is commonly underestimated in clinical practice.
- NLRP3 inflammasome inhibition ameliorates tubulointerstitial injury in the remnant kidney model(2018) FORESTO-NETO, Orestes; AVILA, Victor Ferreira; ARIAS, Simone Costa Alarcon; ZAMBOM, Fernanda Florencia Fregnan; REMPEL, Lisienny Campoli Tono; FAUSTINO, Viviane Dias; MACHADO, Flavia Gomes; MALHEIROS, Denise Maria Avancini Costa; ABENSUR, Hugo; CAMARA, Niels Olsen Saraiva; ZATZ, Roberto; FUJIHARA, Clarice KazueRecent 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 accompanied by increased XOD activity and UA renal levels, associated with augmented heme oxigenase-1 and reduced superoxide dismutase-2 renal contents. Both the NF-kappa B and NLRP3 signaling pathways were activated in Nx. ALLO normalized both XOD activity and the parameters of oxidative stress. ALLO also attenuated hypertension and promoted selective tubulointerstitial protection, reducing urinary NGAL and cortical interstitial injury/inflammation. ALLO reduced renal NLRP3 activation, without interfering with the NF-kappa B pathway. These observations indicate that the tubulointerstitial antiinflammatory and antifibrotic effects of ALLO in the Nx model involve inhibition of the NLRP3 pathway, and reinforce the view that ALLO can contribute to arrest or slow the progression of CKD.
- TLR2 and TLR4 play opposite role in autophagy associated with cisplatin-induced acute kidney injury(2018) ANDRADE-SILVA, Magaiver; CENEDEZE, Marcos Antonio; PERANDINI, Luiz Augusto; FELIZARDO, Raphael Jose Ferreira; WATANABE, Ingrid Kazue Mizuno; AGUDELO, Juan Sebastian Henao; CASTOLDI, Angela; GONCALVES, Giselle Martins; ORIGASSA, Clarice Silvia Taemi; SEMEDO, Patricia; HIYANE, Meire Ioshie; FORESTO-NETO, Orestes; MALHEIROS, Denise Maria Avancini Costa; REIS, Marlene Antonia; FUJIHARA, Clarice Kazue; ZATZ, Roberto; PACHECO-SILVA, Alvaro; CAMARA, Niels Olsen Saraiva; ALMEIDA, Danilo Candido deAcute kidney injury (AKI) is considered an inflammatory disease in which toll-like receptors (TLRs) signaling pathways play an important role. The activation of TLRs results in production of several inflammatory cytokines leading to further renal damage. In contrast, TLRs are key players on autophagy induction, which is associated with a protective function on cisplatin-induced AKI. Hence, the present study aimed to evaluate the specific participation of TLR2 and TLR4 molecules on the development of cisplatin-induced AKI. Complementarily, we also investigated the link between TLRs and heme oxygenase-1 (HO-1), a promisor cytoprotective molecule. First, we observed that only the absence of TLR2 but not TLR4 in mice exacerbated the renal dysfunction, tissue injury and mortality rate, even under an immunologically privileged microenvironment. Second, we demonstrated that TLR2 knockout (KO) mice presented lower expression of autophagy-associated markers when compared with TLR4 KO animals. Similar parameter was confirmed in vitro, using tubular epithelial cells derived from both KO mice. To test the cross-talking between HO-1 and TLRs, hemin (an HO-1 internal inducer) was administrated in cisplatin-treated TLR2 and TLR4 KO mice and it was detected an improvement in the global renal tissue parameters. However, this protection was less evident at TLR2 KO mice. In summary, we documented that TLR2 plays a protective role in cisplatin-induced AKI progression, in part, by a mechanism associated with autophagy up-regulation, considering that its interplay with HO-1 can promote renal tissue recover.
- Simultaneous activation of innate and adaptive immunity participates in the development of renal injury in a model of heavy proteinuria(2018) FAUSTINO, Viviane Dias; ARIAS, Simone Costa Alarcon; AVILA, Victor Ferreira; FORESTO-NETO, Orestes; ZAMBOM, Fernanda Florencia Fregnan; MACHADO, Flavia Gomes; REIS, Luciene Machado dos; MARIA, Denise; VOLPINI, Rildo Aparecido; CAMARA, Niels Olsen Saraiva; ZATZ, Roberto; FUJIHARA, Clarice KazueProtein overload of proximal tubular cells (PTCs) 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 nephropathy (ADR). 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 NE-kappa B 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 observed. Administration of mycophenolate mofetil (MMF), 10 mg/kg/day, prevented activation of both innate and adaptive immunity, as well as renal oxidative stress and renal fibrosis. Moreover, MMF treatment was associated with shifting of M from the M1 to the M2 phenotype. In cultivated NRK52-E cells, excess albumin increased the protein content of Toll-like receptor (TLR) 4 (TLR4), NLRP3, MCP-1, IL6, IL-1 beta Caspase-1, alpha-actin, and collagen-1. Silencing of TLR4 and/or NLRP3 mRNA abrogated this proinflammatory/profibrotic behavior. Simultaneous activation of innate and adaptive immunity may be key to the development of renal injury in heavy proteinuric disease. Inhibition of specific components of innate and/or adaptive immunity may be the basis for future strategies to prevent chronic kidney disease (CKD) in this setting.
- 1,5-Anhydroglucitol predicts CKD progression in macroalbuminuric diabetic kidney disease: results from non-targeted metabolomics(2018) TAVARES, Gesiane; VENTURINI, Gabriela; PADILHA, Kallyandra; ZATZ, Roberto; PEREIRA, Alexandre C.; THADHANI, Ravi I.; RHEE, Eugene P.; TITAN, Silvia M. O.Introduction Metabolomics allows exploration of novel biomarkers and provides insights on metabolic pathways associated with disease. To date, metabolomics studies on CKD have been largely limited to Caucasian populations and have mostly examined surrogate end points. Objective In this study, we evaluated the role of metabolites in predicting a primary outcome defined as dialysis need, doubling of serum creatinine or death in Brazilian macroalbuminuric DKD patients. Methods Non-targeted metabolomics was performed on plasma from 56 DKD patients. Technical triplicates were done. Metabolites were identified using Agilent Fiehn GC/MS Metabolomics and NIST libraries (Agilent MassHunter Work-station Quantitative Analysis, version B. 06.00). After data cleaning, 186 metabolites were left for analyses. Results During a median follow-up time of 2.5 years, the PO occurred in 17 patients (30.3%). In non-parametric testing, 13 metabolites were associated with the PO. In univariate Cox regression, only 1,5-anhydroglucitol (HR 0.10; 95% CI 0.01-0.63, p =.01), norvaline and l-aspartic acid were associated with the PO. After adjustment for baseline renal function, 1,5-anhydroglucitol (HR 0.10; 95% CI 0.02-0.63, p =.01), norvaline (HR 0.01; 95% CI 0.001-0.4, p =.01) and aspartic acid (HR 0.12; 95% CI 0.02-0.64, p =.01) remained significantly and inversely associated with the PO. Conclusion Our results show that lower levels of 1,5-anhydroglucitol, norvaline and l-aspartic acid are associated with progression of macroalbuminuric DKD. While norvaline and l-aspartic acid point to interesting metabolic pathways, 1,5-anhydroglucitol is of particular interest since it has been previously shown to be associated with incident CKD. This inverse biomarker of hyperglycemia should be further explored as a new tool in DKD.
conferenceObject INHIBITION OF THE TLR4/NF-kappa B AXIS ATTENUATED GLOMERULAR INFLAMMATION AND SCLEROSIS IN LONG TERM EXPERIMENTAL DIABETIC KIDNEY DISEASE(2018) FORESTO-NETO, Orestes; ALBINO, Amanda; ARIAS, Simone; FAUSTINO, Viviane; AVILA, Victor; SENA, Claudia; FANELLI, Camilla; VIANA, Vivian; CENEDEZE, Marcos; MACHADO, Flavia; MALHEIROS, Denise; CAMARA, Niels; FUJIHARA, Clarice; ZATZ, Roberto