Polycystin-2 Plays an Essential Role in Glucose Starvation-Induced Autophagy in Human Embryonic Stem Cell-Derived Cardiomyocytes
Publication in refereed journal


摘要Autophagy is a process essential for cell survival under stress condition. The patients with autosomal dominant polycystic kidney disease, which is caused by polycystin‐1 or polycystin‐2 (PKD2) mutation, display cardiovascular abnormalities and dysregulation in autophagy. However, it is unclear whether PKD2 plays a role in autophagy. In the present study, we explored the functional role of PKD2 in autophagy and apoptosis in human embryonic stem cell‐derived cardiomyocytes. HES2 hESC line‐derived cardiomyocytes (HES2‐CMs) were transduced with adenoviral‐based PKD2‐shRNAs (Ad‐PKD2‐shRNAs), and then cultured with normal or glucose‐free medium for 3 hours. Autophagy was upregulated in HES2‐CMs under glucose starvation, as indicated by increased microtubule‐associated protein 1 light chain 3‐II level in immunoblots and increased autophagosome and autolysosome formation. Knockdown of PKD2 reduced the autophagic flux and increased apoptosis under glucose starvation. In Ca2+ measurement, Ad‐PKD2‐shRNAs reduced caffeine‐induced cytosolic Ca2+ rise. Co‐immunoprecipitation and in situ proximity ligation assay demonstrated an increased physical interaction of PKD2 with ryanodine receptor 2 (RyR2) under glucose starvation condition. Furthermore, Ad‐PKD2‐shRNAs substantially attenuated the starvation‐induced activation of AMP‐activated protein kinase (AMPK) and inactivation of mammalian target of rapamycin (mTOR). The present study for the first time demonstrates that PKD2 functions to promote autophagy under glucose starvation, thereby protects cardiomyocytes from apoptotic cell death. The mechanism may involve PKD2 interaction with RyR2 to alter Ca2+ release from sarcoplasmic reticulum, consequently modulating the activity of AMPK and mTOR, resulting in alteration of autophagy and apoptosis.
著者Jun Lu, Kenneth R. Boheler, Liwen Jiang, Camie W. Chan, Wan Wai Tse, Wendy Keung, Ellen Ny Poon, Ronald A. Li, Xiaoqiang Yao
頁次501 - 513

上次更新時間 2021-15-04 於 00:16