PMID- 32730856 OWN - NLM STAT- MEDLINE DCOM- 20211019 LR - 20211204 IS - 1873-3913 (Electronic) IS - 0898-6568 (Linking) VI - 74 DP - 2020 Oct TI - Increased mTOR and suppressed autophagic flux in the heart of a hypomorphic Pkd1 mouse model of autosomal dominant polycystic kidney disease. PG - 109730 LID - S0898-6568(20)30207-2 [pii] LID - 10.1016/j.cellsig.2020.109730 [doi] AB - Cardiac hypertrophy is common in autosomal dominant polycystic kidney disease (ADPKD) patients. We found increased heart weight in Pkd1(RC/RC) and Pkd2(WS25/+) 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 Pkd1(RC/RC) mouse model of PKD. In 70 day old Pkd1(RC/RC) hearts, on immunoblot analysis, there was a large increase in p-AMPK(Thr172), a known autophagy inducer, and an increase in p-Akt(Ser473) and p-Akt(Thr308), but no increase in other mTORC1/2 proteins (p-S6(Ser240/244), p-mTOR(Ser2448)). In 150 day old Pkd1(RC/RC) hearts, there was an increase in mTORC1 (p-S6(Ser240/244)) and mTOR-related proteins (p-Akt(Thr308), p-GSK3beta(Ser9), p-AMPK(Thr172)). 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, Pkd1(RC/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 Pkd1(RC/RC) mice. Increased mTOR signaling in older mice is associated suppressed autophagic flux. There was a large increase in p-AMPK(Thr172), 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. CI - Copyright (c) 2020 Elsevier Inc. All rights reserved. FAU - Atwood, Daniel J AU - Atwood DJ AD - Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA. FAU - Pokhrel, Deepak AU - Pokhrel D AD - Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA. FAU - Brown, Carolyn N AU - Brown CN AD - Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA. FAU - Holditch, Sara J AU - Holditch SJ AD - Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA. FAU - Bachu, Dheevena M AU - Bachu DM AD - Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA. FAU - Thorburn, Andrew AU - Thorburn A AD - Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA. FAU - Hopp, Katharina AU - Hopp K AD - Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA. FAU - Edelstein, Charles L AU - Edelstein CL AD - Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA. Electronic address: Charles.edelstein@cuanschutz.edu. LA - eng GR - I01 BX003803/BX/BLRD VA/United States GR - T32 GM007635/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20200728 PL - England TA - Cell Signal JT - Cellular signalling JID - 8904683 RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Autophagy MH - Cardiomegaly/*metabolism MH - Disease Models, Animal MH - Mice MH - *Polycystic Kidney, Autosomal Dominant/metabolism/pathology MH - TOR Serine-Threonine Kinases/*physiology OTO - NOTNLM OT - Autophagy OT - Autosomal dominant polycystic kidney disease OT - Cardiac hypertrophy OT - Heart OT - mTOR EDAT- 2020/07/31 06:00 MHDA- 2021/10/21 06:00 CRDT- 2020/07/31 06:00 PHST- 2020/06/16 00:00 [received] PHST- 2020/07/22 00:00 [revised] PHST- 2020/07/22 00:00 [accepted] PHST- 2020/07/31 06:00 [pubmed] PHST- 2021/10/21 06:00 [medline] PHST- 2020/07/31 06:00 [entrez] AID - S0898-6568(20)30207-2 [pii] AID - 10.1016/j.cellsig.2020.109730 [doi] PST - ppublish SO - Cell Signal. 2020 Oct;74:109730. doi: 10.1016/j.cellsig.2020.109730. Epub 2020 Jul 28.