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Kidney Int ; 93(1): 54-68, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28964572

RESUMO

The transcription factor MafB is essential for development of the parathyroid glands, the expression of which persists after morphogenesis and in adult parathyroid glands. However, the function of MafB in adult parathyroid tissue is unclear. To investigate this, we induced chronic kidney disease (CKD) in wild-type and MafB heterozygote (MafB+/-) mice by feeding them an adenine-supplemented diet, leading to secondary hyperparathyroidism. The elevated serum creatinine and blood urea nitrogen levels in heterozygous and wild-type mice fed the adenine-supplemented diet were similar. Interestingly, secondary hyperparathyroidism, characterized by serum parathyroid hormone elevation and enlargement of parathyroid glands, was suppressed in MafB+/- mice fed the adenine-supplemented diet compared to similarly fed wild-type littermates. Quantitative RT-PCR and immunohistochemical analyses showed that the increased expression of parathyroid hormone and cyclin D2 in mice with CKD was suppressed in the parathyroid glands of heterozygous CKD mice. A reporter assay indicated that MafB directly regulated parathyroid hormone and cyclin D2 expression. To exclude an effect of a developmental anomaly in MafB+/- mice, we analyzed MafB tamoxifen-induced global knockout mice. Hypocalcemia-stimulated parathyroid hormone secretion was significantly impaired in MafB knockout mice. RNA-sequencing analysis indicated PTH, Gata3 and Gcm2 depletion in the parathyroid glands of MafB knockout mice. Thus, MafB appears to play an important role in secondary hyperparathyroidism by regulation of parathyroid hormone and cyclin D2 expression. Hence, MafB may represent a new therapeutic target in secondary hyperparathyroidism.


Assuntos
Hiperparatireoidismo Secundário/metabolismo , Fator de Transcrição MafB/metabolismo , Glândulas Paratireoides/metabolismo , Animais , Nitrogênio da Ureia Sanguínea , Cálcio/sangue , Creatinina/sangue , Ciclina D2/genética , Ciclina D2/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Hiperparatireoidismo Secundário/sangue , Hiperparatireoidismo Secundário/genética , Hiperparatireoidismo Secundário/patologia , Hipocalcemia/genética , Hipocalcemia/metabolismo , Fator de Transcrição MafB/deficiência , Fator de Transcrição MafB/genética , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glândulas Paratireoides/patologia , Hormônio Paratireóideo/sangue , Hormônio Paratireóideo/genética
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