LIM/29 - Laboratório de Nefrologia Celular, Genética e Molecular
URI Permanente desta comunidade
O Laboratório de Nefrologia Celular, Genética e Molecular é ligado ao Departamento de Clínica Médica da Faculdade de Medicina da Universidade de São Paulo (FMUSP).
Linhas de pesquisa: patogênese molecular e celular da doença renal policística autossômica recessiva; células-tronco e doenças renais; mecanismos inflamatórios envolvidos na fibrogênese das doenças renais e análise de estratégias antifibróticas; e mecanismos envolvidos na rejeição e tolerância ao enxerto em transplante de órgãos: rim, pâncreas e transplante experimental de rim e ilhotas pancreáticas.
Site oficial: http://limhc.fm.usp.br/portal/lim29-laboratorio-de-nefrologia-celular-genetica-e-molecular/
Linhas de pesquisa: patogênese molecular e celular da doença renal policística autossômica recessiva; células-tronco e doenças renais; mecanismos inflamatórios envolvidos na fibrogênese das doenças renais e análise de estratégias antifibróticas; e mecanismos envolvidos na rejeição e tolerância ao enxerto em transplante de órgãos: rim, pâncreas e transplante experimental de rim e ilhotas pancreáticas.
Site oficial: http://limhc.fm.usp.br/portal/lim29-laboratorio-de-nefrologia-celular-genetica-e-molecular/
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- LIM/29 - Laboratório de Nefrologia Celular, Genética e Molecular
- LIM/29 - Laboratório de Nefrologia Celular, Genética e Molecular
- LIM/29 - Laboratório de Nefrologia Celular, Genética e Molecular
Submissões Recentes
WT1 Pathogenic Variants are Associated with a Broad Spectrum of Differences in Sex Development Phenotypes and Heterogeneous Progression of Renal Disease
(2022) FERRARI, M. T. M.; WATANABE, A.; SILVA, T. E. Da; GOMES, N. L.; BATISTA, R. L.; NISHI, M. Y.; PAULA, L. C. P. De; COSTA, E. C.; COSTA, E. M. F.; CUKIER, P.; ONUCHIC, L. F.; MENDONCA, B. B.; DOMENICE, S.
Wilms' tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Heterozygous germline pathogenic allelic variants of WT1 have been classically associated with Denys-Drash syndrome (DDS) and Frasier syndrome (FS). Usually, exonic pathogenic missense variants in the zinc finger region are the cause of DDS, whereas pathogenic variants affecting the canonic donor lysine-threonine-serine splice site in intron 9 cause FS. Phenotypic overlap between WT1 disorders has been frequently observed. New WT1 variant-associated phenotypes, such as 46,XX testicular/ovarian-testicular disorders of sex development (DSD) and primary ovarian insufficiency, have been reported. In this report, we describe the phenotypes and genotypes of 7 Brazilian patients with pathogenic WT1 variants. The molecular study involved Sanger sequencing and massively parallel targeted sequencing using a DSD-associated gene panel. Six patients (5 with a 46,XY karyotype and 1 with a 46,XX karyotype) were initially evaluated for atypical genitalia, and a 46,XY patient with normal female genitalia sought medical attention for primary amenorrhea. Germ cell tumors were identified in 2 patients, both with variants affecting alternative splicing of WT1 between exons 9 and 10. Two pathogenic missense WT1 variants were identified in two 46,XY individuals with Wilms' tumors; both patients were <1 year of age at the time of diagnosis. A novel WT1 variant, c.1453_1456 (p.Arg485Glyfs∗14), was identified in a 46,XX patient with testicular DSD. Nephrotic proteinuria was diagnosed in all patients, including 3 who underwent renal transplantation after progressing to end-stage kidney disease. The expanding phenotypic spectrum associated with WT1 variants in XY and XX individuals confirms their pivotal role in gonadal and renal development as well as in tumorigenesis, emphasizing the clinical implications of these variants in genetic diagnosis.
Mitochondrial Calcium Dynamics and Bioenergetics in Autosomal Dominant Polycystic Kidney Disease: more pieces to the puzzle
(2023) AMARAL, Andressa; SERNA, Julian David Cualcialpud; SILVA, Camille C. Caldeira da; COSTA, Eliene; ONUCHIC, Luiz Fernando; KOWALTOWSKI, Alicia
ANCA-associated glomerulonephritis and lupus nephritis following COVID-19 vaccination: a case report and literature review
(2024) CAMPOS, Marcos Adriano Garcia; VALOIS, Tiago de Oliveira; MAGALHAES, Luis Eduardo; VASQUES, Lucas Fernandes; MEDEIROS, Rafael Goulart de; COSTA, Denise Maria do Nascimento; SALGADO FILHO, Natalino; NOGUEIRA, Raquel Moraes da Rocha; NEVES, Precil Diego Miranda de Menezes; SILVA, Gyl Eanes Barros
With the coverage of COVID-19 vaccination, it has been possible to observe the potential side effects of SARS-CoV-2 vaccines, with the most common ones being fever, myalgia, headache, and fatigue. However, an association has been observed between new and recurrent kidney injuries, mainly glomerulonephritis and lupus nephritis associated with ANCA, with the Pfizer-BioNTech, Moderna, Sinovac, and AstraZeneca vaccines, although the relationship between them is not clear. We report a case of ANCA-related vasculitis and lupus glomerulonephritis after the second dose of the AstraZeneca vaccine. The elderly patient presented significant worsening of kidney function after immunosuppression and complications after a new onset COVID-19 infection that led to death. We provide a literature review about kidney damage related to ANCA vasculitis after COVID-19 vaccine, aiming for a better understanding of the pathophysiological mechanism of kidney injury, its presentation, and treatment.
Effects of early exercise on cardiac function and lipid metabolism pathway in heart failure
(2023) SOUZA, Sergio Luiz Borges de; MOTA, Gustavo Augusto Ferreira; SILVA, Vitor Loureiro da; VILEIGAS, Danielle Fernandes; SANT'ANA, Paula Grippa; GREGOLIN, Cristina Schmitt; FIGUEIRA, Rebeca Lopes; BATAH, Sabrina Setembre; FABRO, Alexandre Todorovic; MURATA, Gilson Masahiro; BAZAN, Silmeia Garcia Zanati; OKOSHI, Marina Politi; CICOGNA, Antonio Carlos
We employed an early training exercise program, immediately after recovery from surgery, and before severe cardiac hypertrophy, to study the underlying mechanism involved with the amelioration of cardiac dysfunction in aortic stenosis (AS) rats. As ET induces angiogenesis and oxygen support, we aimed to verify the effect of exercise on myocardial lipid metabolism disturbance. Wistar rats were divided into Sham, trained Sham (ShamT), AS and trained AS (AST). The exercise consisted of 5-week sessions of treadmill running for 16 weeks. Statistical analysis was conducted by anova or Kruskal-Wallis test and Goodman test. A global correlation between variables was also performed using a two-tailed Pearson's correlation test. AST rats displayed a higher functional capacity and a lower cardiac remodelling and dysfunction when compared to AS, as well as the myocardial capillary rarefaction was prevented. Regarding metabolic properties, immunoblotting and enzymatic assay raised beneficial effects of exercise on fatty acid transport and oxidation pathways. The correlation assessment indicated a positive correlation between variables of angiogenesis and FA utilisation, as well as between metabolism and echocardiographic parameters. In conclusion, early exercise improves exercise tolerance and attenuates cardiac structural and functional remodelling. In parallel, exercise attenuated myocardial capillary and lipid metabolism derangement in rats with aortic stenosis-induced heart failure.
The influence of dapagliflozin on cardiac remodeling, myocardial function and metabolomics in type 1 diabetes mellitus rats
(2023) RODRIGUES, Eder Anderson; ROSA, Camila Moreno; CAMPOS, Dijon Henrique Salome; DAMATTO, Felipe Cesar; MURATA, Gilson Masahiro; SOUZA, Lidiane Moreira; PAGAN, Luana Urbano; GATTO, Mariana; BROSLER, Jessica Yumi; SOUZA, Hebreia Oliveira Almeida; MARTINS, Mario Machado; BASTOS, Luciana Machado; TANNI, Suzana Erico; OKOSHI, Katashi; OKOSHI, Marina Politi
BackgroundSodium-glucose cotransporter (SGLT)2 inhibitors have displayed beneficial effects on the cardiovascular system in diabetes mellitus (DM) patients. As most clinical trials were performed in Type 2 DM, their effects in Type 1 DM have not been established.ObjectiveTo evaluate the influence of long-term treatment with SGLT2 inhibitor dapagliflozin on cardiac remodeling, myocardial function, energy metabolism, and metabolomics in rats with Type 1 DM.MethodsMale Wistar rats were divided into groups: Control (C, n = 15); DM (n = 15); and DM treated with dapagliflozin (DM + DAPA, n = 15) for 30 weeks. DM was induced by streptozotocin. Dapagliflozin 5 mg/kg/day was added to chow. Statistical analysis: ANOVA and Tukey or Kruskal-Wallis and Dunn.ResultsDM + DAPA presented lower glycemia and higher body weight than DM. Echocardiogram showed DM with left atrium dilation and left ventricular (LV) hypertrophy, dilation, and systolic and diastolic dysfunction. In LV isolated papillary muscles, DM had reduced developed tension, +dT/dt and -dT/dt in basal condition and after inotropic stimulation. All functional changes were attenuated by dapagliflozin. Hexokinase (HK), phosphofructokinase (PFK) and pyruvate kinase (PK) activity was lower in DM than C, and PFK and PK activity higher in DM + DAPA than DM. Metabolomics revealed 21 and 5 metabolites positively regulated in DM vs. C and DM + DAPA vs. DM, respectively; 6 and 3 metabolites were negatively regulated in DM vs. C and DM + DAPA vs. DM, respectively. Five metabolites that participate in cell membrane ultrastructure were higher in DM than C. Metabolites levels of N-oleoyl glutamic acid, chlorocresol and N-oleoyl-L-serine were lower and phosphatidylethanolamine and ceramide higher in DM + DAPA than DM.ConclusionLong-term treatment with dapagliflozin attenuates cardiac remodeling, myocardial dysfunction, and contractile reserve impairment in Type 1 diabetic rats. The functional improvement is combined with restored pyruvate kinase and phosphofructokinase activity and attenuated metabolomics changes.
Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial
(2023) ROVIN, Brad H.; BARRATT, Jonathan; HEERSPINK, Hiddo J. L.; ALPERS, Charles E.; BIELER, Stewart; CHAE, Dong-Wan; DIVA, Ulysses A.; FLOEGE, Juergen; GESUALDO, Loreto; INRIG, Jula K.; KOHAN, Donald E.; KOMERS, Radko; KOOIENGA, Laura Ann; LAFAYETTE, Richard; MAES, Bart; MALECKI, Robert; MERCER, Alex; NORONHA, Irene L.; OH, Se Won; PEH, Chen Au; PRAGA, Manuel; PRECIADO, Priscila; RADHAKRISHNAN, Jai; RHEAULT, Michelle N.; ROTE, William E.; TANG, Sydney C. W.; TESAR, Vladimir; TRACHTMAN, Howard; TRIMARCHI, Hernan; TUMLIN, James A.; WONG, Muh Geot; PERKOVIC, Vlado
Background Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function , outcomes over 110 weeks from the double-blind final analysis. Methods PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia , Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1 center dot 0 g per day despite maximised renin-angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850.Findings Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6-110) was -2 center dot 7 mL/min per 1 center dot 73 m2 per year versus -3 center dot 8 mL/min per 1 center dot 73 m2 per year (difference 1 center dot 1 mL/min per 1 center dot 73 m2 per year, 95% CI 0 center dot 1 to 2 center dot 1; p=0 center dot 037); total 2-year slope (day 1-week 110) was -2 center dot 9 mL/min per 1 center dot 73 m2 per year versus -3 center dot 9 mL/min per 1 center dot 73 m2 per year (difference 1 center dot 0 mL/min per 1 center dot 73 m2 per year, 95% CI -0 center dot 03 to 1 center dot 94; p=0 center dot 058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (-42 center dot 8%, 95% CI -49 center dot 8 to -35 center dot 0, with sparsentan versus -4 center dot 4%, -15 center dot 8 to 8 center dot 7, with irbesartan; geometric least-squares mean ratio 0 center dot 60, 95% CI 0 center dot 50 to 0 center dot 72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0 center dot 7, 95% CI 0 center dot 4 to 1 center dot 2). Treatment -emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. Interpretation Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function.
Integrated control strategies for dengue, Zika, and Chikungunya virus infections
(2023) CORTES, Nelson; LIRA, Aline; PRATES-SYED, Wasim; SILVA, Jaqueline Dinis; VUITIKA, Larissa; CABRAL-MIRANDA, William; DURAES-CARVALHO, Ricardo; BALAN, Andrea; CABRAL-MARQUES, Otavio; CABRAL-MIRANDA, Gustavo
Arboviruses are a major threat to public health in tropical regions, encompassing over 534 distinct species, with 134 capable of causing diseases in humans. These viruses are transmitted through arthropod vectors that cause symptoms such as fever, headache, joint pains, and rash, in addition to more serious cases that can lead to death. Among the arboviruses, dengue virus stands out as the most prevalent, annually affecting approximately 16.2 million individuals solely in the Americas. Furthermore, the re-emergence of the Zika virus and the recurrent outbreaks of chikungunya in Africa, Asia, Europe, and the Americas, with one million cases reported annually, underscore the urgency of addressing this public health challenge. In this manuscript we discuss the epidemiology, viral structure, pathogenicity and integrated control strategies to combat arboviruses, and the most used tools, such as vaccines, monoclonal antibodies, treatment, etc., in addition to presenting future perspectives for the control of arboviruses. Currently, specific medications for treating arbovirus infections are lacking, and symptom management remains the primary approach. However, promising advancements have been made in certain treatments, such as Chloroquine, Niclosamide, and Isatin derivatives, which have demonstrated notable antiviral properties against these arboviruses in vitro and in vivo experiments. Additionally, various strategies within vector control approaches have shown significant promise in reducing arbovirus transmission rates. These encompass public education initiatives, targeted insecticide applications, and innovative approaches like manipulating mosquito bacterial symbionts, such as Wolbachia. In conclusion, combatting the global threat of arbovirus diseases needs a comprehensive approach integrating antiviral research, vaccination, and vector control. The continued efforts of research communities, alongside collaborative partnerships with public health authorities, are imperative to effectively address and mitigate the impact of these arboviral infections on public health worldwide.
Neuroimmunology of rabies: New insights into an ancient disease
(2023) BASTOS, Victor; PACHECO, Vinicius; RODRIGUES, Erika D. L.; MORAES, Cassia N. S.; NOBILE, Adriel L.; FONSECA, Dennyson Leandro M.; SOUZA, Kamilla B. S.; VALE, Fernando Y. N. do; FILGUEIRAS, Igor S.; SCHIMKE, Lena F.; GIIL, Lasse M.; MOLL, Guido; CABRAL-MIRANDA, Gustavo; OCHS, Hans D.; VASCONCELOS, Pedro F. da Costa; MELO, Guilherme D. de; BOURHY, Herve; CASSEB, Livia M. N.; CABRAL-MARQUES, Otavio
Rabies is an ancient neuroinvasive viral (genus Lyssavirus, family Rhabdoviridae) disease affecting approximately 59,000 people worldwide. The central nervous system (CNS) is targeted, and rabies has a case fatality rate of almost 100% in humans and animals. Rabies is entirely preventable through proper vaccination, and thus, the highest incidence is typically observed in developing countries, mainly in Africa and Asia. However, there are still cases in European countries and the United States. Recently, demographic, increasing income levels, and the coronavirus disease 2019 (COVID-19) pandemic have caused a massive raising in the animal population, enhancing the need for preventive measures (e.g., vaccination, surveillance, and animal control programs), postexposure prophylaxis, and a better understanding of rabies pathophysiology to identify therapeutic targets, since there is no effective treatment after the onset of clinical manifestations. Here, we review the neuroimmune biology and mechanisms of rabies. Its pathogenesis involves a complex and poorly understood modulation of immune and brain functions associated with metabolic, synaptic, and neuronal impairments, resulting in fatal outcomes without significant histopathological lesions in the CNS. In this context, the neuroimmunological and neurochemical aspects of excitatory/inhibitory signaling (e.g., GABA/glutamate crosstalk) are likely related to the clinical manifestations of rabies infection. Uncovering new links between immunopathological mechanisms and neurochemical imbalance will be essential to identify novel potential therapeutic targets to reduce rabies morbidity and mortality.
A short-term high-sugar diet is an aggravating factor in experimental allergic contact dermatitis
(2023) COELHO, Leila F.; CASARO, Mateus B.; RIBEIRO, Willian R.; MENDES, Eduardo; MURATA, Gilson; XANDER, Patricia; LINO-DOS-SANTOS-FRANCO, Adriana; OLIVEIRA, Fernando A.; FERREIRA, Caroline M.
Allergic contact dermatitis (ACD) is an inflammatory skin reaction whose incidence has increased and has been associated with a dietary pattern rich in saturated fats and refined sugars. Considering the increased incidence of ACD and the lack of research about the influence of a short-term high-sugar diet on dermatitis, our aim is to improve understanding of the influence of a high-sugar diet on ACD. We introduced a diet rich in sugar fifteen days before inducing contact dermatitis with oxazolone, in mice, and maintained it until the end of the experiment, which lasted three weeks in total. The dermatitis model increased cholesterol and triglycerides in the liver, and the combination of diet and dermatitis increased weight and worsened liver cholesterol measurements. Furthermore, the high-sugar diet increased the production of IL-6, IFN-gamma and TNF alpha in the skin, which may be involved in the increase in epithelial skin thickness observed in experimental ACD.
Changes in Skeletal Muscle Protein Metabolism Signaling Induced by Glutamine Supplementation and Exercise
(2023) JR, Carlos Flores Rodrigues; MURATA, Gilson Masahiro; GERLINGER-ROMERO, Frederico; NACHBAR, Renato Tadeu; MARZUCA-NASSR, Gabriel Nasri; GORJAO, Renata; VITZEL, Kaio Fernando; HIRABARA, Sandro Massao; PITHON-CURI, Tania Cristina; CURI, Rui
Aim: To evaluate the effects of resistance exercise training (RET) and/or glutamine supplementation (GS) on signaling protein synthesis in adult rat skeletal muscles. Methods: The following groups were studied: (1) control, no exercise (C); (2) exercise, hypertrophy resistance exercise training protocol (T); (3) no exercise, supplemented with glutamine (G); and (4) exercise and supplemented with glutamine (GT). The rats performed hypertrophic training, climbing a vertical ladder with a height of 1.1 m at an 80 degrees incline relative to the horizontal with extra weights tied to their tails. The RET was performed three days a week for five weeks. Each training session consisted of six ladder climbs. The extra weight load was progressively increased for each animal during each training session. The G groups received daily L-glutamine by gavage (one g per kilogram of body weight per day) for five weeks. The C group received the same volume of water during the same period. The rats were euthanized, and the extensor digitorum longus (EDL) muscles from both hind limbs were removed and immediately weighed. Glutamine and glutamate concentrations were measured, and histological, signaling protein contents, and mRNA expression analyses were performed. Results: Supplementation with free L-glutamine increased the glutamine concentration in the EDL muscle in the C group. The glutamate concentration was augmented in the EDL muscles from T rats. The EDL muscle mass did not change, but a significant rise was reported in the cross-sectional area (CSA) of the fibers in the three experimental groups. The levels of the phosphorylated proteins (pAkt/Akt, pp70S6K/p70S6K, p4E-BP1/4E-BP1, and pS6/S6 ratios) were significantly increased in EDL muscles of G rats, and the activation of p4E-BP1 was present in T rats. The fiber CSAs of the EDL muscles in T, G, and GT rats were increased compared to the C group. These changes were accompanied by a reduction in the 26 proteasome activity of EDL muscles from T rats. Conclusion: Five weeks of GS and/or RET induced muscle hypertrophy, as indicated by the increased CSAs of the EDL muscle fibers. The increase in CSA was mediated via the upregulated phosphorylation of Akt, 4E-BP1, p70S6k, and S6 in G animals and 4E-BP1 in T animals. In the EDL muscles from T animals, a decrease in proteasome activity, favoring a further increase in the CSA of the muscle fibers, was reported.