Blocking hyperactive androgen receptor signaling ameliorates cardiac and renal hypertrophy in Fabry mice

Jin Song Shen, Xing Li Meng, Mary Wight-Carter, Taniqua S. Day, Sean C. Goetsch, Sabrina Forni, Jay W. Schneider, Zhi Ping Liu, Raphael Schiffmann

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11 Scopus citations

Abstract

Fabry disease is caused by deficient activity of lysosomal enzyme α-galactosidase A. The enzyme deficiency results in intracellular accumulation of glycosphingolipids, leading to a variety of clinical manifestations including hypertrophic cardiomyopathy and renal insufficiency. The mechanism through which glycosphingolipid accumulation causes these manifestations remains unclear. Current treatment, especially when initiated at later stage of the disease, does not produce completely satisfactory results. Elucidation of the pathogenesis of Fabry disease is therefore crucial to developing new treatments.We found increased activity of androgen receptor (AR) signaling in Fabry disease.We subsequently also found that blockade of AR signaling either through castration or AR-antagonist prevented and reversed cardiac and kidney hypertrophic phenotype in a mouse model of Fabry disease. Our findings implicate abnormal AR pathway in the pathogenesis of Fabry disease and suggest blocking AR signaling as a novel therapeutic approach.

Original languageEnglish (US)
Article numberddv070
Pages (from-to)3181-3191
Number of pages11
JournalHuman Molecular Genetics
Volume24
Issue number11
DOIs
StatePublished - Dec 15 2014

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ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Shen, J. S., Meng, X. L., Wight-Carter, M., Day, T. S., Goetsch, S. C., Forni, S., Schneider, J. W., Liu, Z. P., & Schiffmann, R. (2014). Blocking hyperactive androgen receptor signaling ameliorates cardiac and renal hypertrophy in Fabry mice. Human Molecular Genetics, 24(11), 3181-3191. [ddv070]. https://doi.org/10.1093/hmg/ddv070