Cardiac dysfunction in Pkd1-deficient mice with phenotype rescue by galectin-3 knockout

Balbo, Bruno Eduardo Pedroso; Amaral, Andressa Godoy; Fonseca, Jonathan M.; Castro, Isac de; Salemi, V. M. C.; Souza, Leandro Franco de; Santos, Fernando dos; Irigoyen, Maria Cláudia; Qian, Feng; Chammas, Roger; Onuchic, Luiz Fernando

doi:10.1016/j.kint.2016.04.028

Cited by 26 publications

(31 citation statements)

References 49 publications

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“…A clear decrease with cardiac dysfunctions, PKD1, and ZMPSTE24 was revealed as a function of dose. Interestingly, deficiencies or decreases in both PKD1 [63] and ZMPSTE24 [64] expression have been previously shown to cause cardiac dysfunction. These observed biological functions seem to follow a trend that may have be missed by manual analysis.…”

Section: Gsea C2: Curated Dataset Resultsmentioning

confidence: 99%

NASA GeneLab Platform Utilized for Biological Response to Space Radiation in Animal Models

McDonald¹,

Stainforth

Cahill

et al. 2020

Cancers

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Background: Ionizing radiation from galactic cosmic rays (GCR) is one of the major risk factors that will impact the health of astronauts on extended missions outside the protective effects of the Earth’s magnetic field. The NASA GeneLab project has detailed information on radiation exposure using animal models with curated dosimetry information for spaceflight experiments. Methods: We analyzed multiple GeneLab omics datasets associated with both ground-based and spaceflight radiation studies that included in vivo and in vitro approaches. A range of ions from protons to iron particles with doses from 0.1 to 1.0 Gy for ground studies, as well as samples flown in low Earth orbit (LEO) with total doses of 1.0 mGy to 30 mGy, were utilized. Results: From this analysis, we were able to identify distinct biological signatures associating specific ions with specific biological responses due to radiation exposure in space. For example, we discovered changes in mitochondrial function, ribosomal assembly, and immune pathways as a function of dose. Conclusions: We provided a summary of how the GeneLab’s rich database of omics experiments with animal models can be used to generate novel hypotheses to better understand human health risks from GCR exposures.

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Section: Gsea C2: Curated Dataset Resultsmentioning

confidence: 99%

NASA GeneLab Platform Utilized for Biological Response to Space Radiation in Animal Models

McDonald¹,

Stainforth

Cahill

et al. 2020

Cancers

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“… 24 , 43 Increased cardiomyocyte apoptosis and reduced LVEF have also been observed in a Pkd1- haploinsufficient mouse model. 44 Polycystin-1 promotes stabilization of L-type calcium channels, and myocardial function is impaired in Pkd1 -deficient mice. 43 , 44 Overexpression of the ≈200-aa, cytoplasmic C-terminal tail of polycystin-1 is sufficient to promote cardiomyocyte hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

“… 44 Polycystin-1 promotes stabilization of L-type calcium channels, and myocardial function is impaired in Pkd1 -deficient mice. 43 , 44 Overexpression of the ≈200-aa, cytoplasmic C-terminal tail of polycystin-1 is sufficient to promote cardiomyocyte hypertrophy. 43 In addition to renal and hepatic cystic disease, mice overexpressing a Pkd1 transgene develop an eccentric dilated cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

Autosomal Dominant Polycystic Kidney Patients May Be Predisposed to Various Cardiomyopathies

Chebib

Hogan

El-Zoghby

et al. 2017

Kidney International Reports

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IntroductionMutations in PKD1 and PKD2 cause autosomal dominant polycystic kidney disease (ADPKD). Experimental evidence suggests an important role of the polycystins in cardiac development and myocardial function. To determine whether ADPKD may predispose to the development of cardiomyopathy, we have evaluated the coexistence of diagnoses of ADPKD and primary cardiomyopathy in our patients.MethodsClinical data were retrieved from medical records for patients with a coexisting diagnosis of ADPKD and cardiomyopathies evaluated at the Mayo Clinic (1984–2015).ResultsAmong the 58 of 667 patients with available echocardiography data, 39 (5.8%) had idiopathic dilated cardiomyopathy (IDCM), 17 (2.5%) had hypertrophic obstructive cardiomyopathy, and 2 (0.3%) had left ventricular noncompaction. Genetic data were available for 19, 8, and 2 cases of IDCM, hypertrophic obstructive cardiomyopathy, and left ventricular noncompaction, respectively. PKD1 mutations were detected in 42.1%, 62.5%, and 100% of IDCM, hypertrophic obstructive cardiomyopathy, and left ventricular noncompaction cases, respectively. PKD2 mutations were detected only in IDCM cases and were overrepresented (36.8%) relative to the expected frequency in ADPKD (15%). In at least 1 patient from 3 IDMC families and 1 patient from a hypertrophic obstructive cardiomyopathy family, the cardiomyopathy did not segregate with ADPKD, suggesting that the PKD mutations may be predisposing factors rather than solely responsible for the development of cardiomyopathy.DiscussionCoexistence of ADPKD and cardiomyopathy in our tertiary referral center cohort appears to be higher than expected by chance. We suggest that PKD1 and PKD2 mutations may predispose to primary cardiomyopathies and that genetic interactions may account for the observed coexistence of ADPKD and cardiomyopathies.

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“…Mais recentemente, por fim, Paavola e cols observaram maior prevalência de cardiomiopatia dilatada idiopática (CMDI) em pacientes DRPAD, principalmente com mutações em PKD2 (DRPAD2). Vale notar que CMDI foi detectada em pacientes DRPAD2 hipertensos e normotensos (107).Nesse cenário, estudos recentes voltaram-se à elucidação mais profunda dos mecanismos envolvidos na determinação e evolução do fenótipo cardíaco associado à DRPAD.Um importante estudo conduzido por Balbo e cols em nosso laboratório mostrou que camundongos haploinsuficientes para Pkd1 (Pkd1 +/-), animais não císticos e normotensos, apresentaram disfunção sistólica e redução da deformação miocárdica, caracterizadas por diminuição da fração de ejeção do ventrículo esquerdo (FEVE) e redução de strain e strain rate(108). Camundongos císticos hipertensos Pkd1 flox/flox :Nestin cre , por sua vez, apresentaram não apenas diminuição de FEVE e de deformabilidade cardíaca, como também aumento da relação entre as ondas E/A e do tempo de desaceleração da válvula mitral, alterações consistentes com disfunção diastólica(108).…”

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“…-em diferentes modelos animais de deficiência de Pkd1(108). Vale notar que um desses modelos foi o camundongo VV.Figura 10).…”

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Camundongos deficientes em Pkd1 apresentam disfunção cardíaca associada a reprogramação metabólica e aumento de inflamação e apoptose

Amaral¹

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Aos meus pais, Marcos e Cida, pelo amor, incentivo e apoio incondicional. Ao meu marido, Edwin, por ter aceitado e vivido esse sonho comigo, mesmo que lhe fugindo a razão. Agradecimentos À minha irmã Thais e meu cunhado Carlo por terem me acolhido em sua casa quando vim para São Paulo e minha vida era cheia de incertezas. Por terem me transformado na tia Dessa, a melhor versão de mim mesma! Aos meus sobrinhos, que mesmo sem saberem, me consolaram em momentos de dificuldades, deixando minha vida muito mais colorida e alegre! Ao Professor Luiz Fernando Onuchic pelas oportunidades, ensinamentos, conselhos e pelo entusiasmo científico que muito me motivaram nessa jornada. À Prof a Alicia Kowaltovski pela colaboração, por ter feito renascer em mim a paixão pela pesquisa e principalmente pelo exemplo de pesquisadora, minha enorme gratidão e admiração. Ao Prof. Kinulpe Sampaio pelo auxílio na microscopia eletrônica e pelos bons momentos proporcionados em Belo Horizonte. Ao Dr. Maurício Sforça, Dra Silvana Rocco e Dr. Antônio Bloise pelo auxílio nos experimentos e análises de metabolômica. À Dra Ana Maria Gonçalves da Silva pelos ensinamentos em imunohistoquímica, pelo exemplo de excelência e pela amizade. Ao Dr. Amaro Duarte Neto, médico patologista, pela dedicação e pelo auxílio nas análises histológicas. À Prof a Silvana Bordin e Dr. Gilson Murata pela gentileza em ceder diversos anticorpos utilizados neste trabalho.

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Cardiac dysfunction in Pkd1-deficient mice with phenotype rescue by galectin-3 knockout

Cited by 26 publications

References 49 publications

NASA GeneLab Platform Utilized for Biological Response to Space Radiation in Animal Models

NASA GeneLab Platform Utilized for Biological Response to Space Radiation in Animal Models

Autosomal Dominant Polycystic Kidney Patients May Be Predisposed to Various Cardiomyopathies

Camundongos deficientes em Pkd1 apresentam disfunção cardíaca associada a reprogramação metabólica e aumento de inflamação e apoptose

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