Increased mTOR and suppressed autophagic flux in the heart of a hypomorphic Pkd1 mouse model of autosomal dominant polycystic kidney disease |
| |
| Institution: | 1. Instituto de Investigación en Ciencias Odontológicas (ICOD), Facultad de Odontología, Universidad de Chile, Santiago, Chile;2. Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile;3. Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile;4. Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile;5. Cardiology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States;1. Department of Human Genetics, Leiden University Medical Centre, Leiden, the Netherlands;2. Division of Nephrology, University Health Network, Toronto, Ontario, Canada;3. Laboratory Medicine and Pathobiology, University Health Network, Toronto, Ontario, Canada;4. Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada;5. Division of Nephrology, University of Toronto, Toronto, Ontario, Canada;6. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada;1. Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA;2. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA;3. Advanced Center for Chronic Diseases (ACCDiS), Center for Exercise, Metabolism and Cancer Studies (CEMC), Universidad de Chile, Chile;4. Instituto de Investigación en Ciencias Odontológicas (ICOD), Facultad de Odontología, Universidad de Chile, Chile;5. Instituto de Ciencias Biomédicas, Facultad Medicina, Universidad de Chile, Chile;6. Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile;7. Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile;8. Department of Internal Medicine, Yale University, New Haven, CT, USA;9. Department of Molecular Cell Biology, Katholieke Universiteit Leuven, Leuven 3000, Belgium;10. Department of Advanced Biomedical Sciences, Federico II University, Via Pansini 5, 80131 Naples, Italy |
| |
| Abstract: | Cardiac hypertrophy is common in autosomal dominant polycystic kidney disease (ADPKD) patients. We found increased heart weight in Pkd1RC/RC and Pkd2WS25/+ mouse models of ADPKD. As there is a link between increased heart weight and mammalian target of rapamycin (mTOR), the aim of the study was to determine mTOR complex 1 and 2 signaling proteins in the heart in the Pkd1RC/RC mouse model of PKD. In 70 day old Pkd1RC/RC hearts, on immunoblot analysis, there was a large increase in p-AMPKThr172, a known autophagy inducer, and an increase in p-AktSer473 and p-AktThr308, but no increase in other mTORC1/2 proteins (p-S6Ser240/244, p-mTORSer2448). In 150 day old Pkd1RC/RC hearts, there was an increase in mTORC1 (p-S6Ser240/244) and mTOR-related proteins (p-AktThr308, p-GSK3βSer9, p-AMPKThr172). As the mTOR pathway is the master regulator of autophagy, autophagy proteins were measured. There was an increase in p-Beclin-1 (BECN1), an autophagy regulator and activating molecule in Beclin-1-regulated autophagy (AMBRA1), a regulator of Beclin that play a role in autophagosome formation, an early stage of autophagy. There was a defect in the later stage of autophagy, the fusion of the autophagosome with the lysosome, known as autophagic flux, as evidenced by the lack of an increase in LC3-II, a marker of autophagosomes, with the lysosomal inhibitor bafilomycin, in both 70 day old and 150 day old hearts. To determine the role of autophagy in causing increased heart weight, Pkd1RC/RC were treated with 2-deoxyglucose (2-DG) or Tat-Beclin1 peptide, agents known to induce autophagy. 2-DG treatment from 150 to 350 days of age, a time period when increased heart weight developed, did not reduce the increased heart weight. Unexpectedly, Tat-Beclin 1 peptide treatment from 70 to 120 days of age resulted in increased heart weight. In summary, there is suppressed autophagic flux in the heart at an early age in Pkd1RC/RC mice. Increased mTOR signaling in older mice is associated suppressed autophagic flux. There was a large increase in p-AMPKThr172, a known autophagy inducer, in both young and old mice. 2-DG treatment did not impact increased heart weight and Tat-Beclin1 peptide increased heart weight. |
| |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
