PMID- 34700229 OWN - NLM STAT- MEDLINE DCOM- 20220125 LR - 20220125 IS - 1950-6007 (Electronic) IS - 0753-3322 (Linking) VI - 144 DP - 2021 Dec TI - Rapamycin attenuates PLA2R activation-mediated podocyte apoptosis via the PI3K/AKT/mTOR pathway. PG - 112349 LID - S0753-3322(21)01133-1 [pii] LID - 10.1016/j.biopha.2021.112349 [doi] AB - Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults without diabetes. Primary MN has been associated with circulating antibodies against native podocyte antigens, including phospholipase A2 receptor (PLA2R); however, precision therapy targeting the signaling cascade of PLA2R activation is lacking. Both PLA2R and the mammalian target of rapamycin (mTOR) exist in podocytes, but the interplay between these two proteins and their roles in MN warrants further exploration. This study aimed to investigate the crosstalk between PLA2R activation and mTOR signaling in a human podocyte cell line. We demonstrated that podocyte apoptosis was induced by Group IB secretory phospholipase A2 (sPLA2IB) in a concentration- and time-dependent manner via upregulation of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and mTOR, and inhibited by rapamycin or LY294002. Furthermore, aberrant activation of the PI3K/AKT/mTOR pathway triggers both extrinsic (caspase-8 and caspase-3) and intrinsic (Bcl-2-associated X protein [BAX], B-cell lymphoma 2 [BCL-2], cytochrome c, caspase-9, and caspase-3) apoptotic cascades in podocytes. The therapeutic implications of our findings are that strategies to reduce PLA2R activation and PI3K/AKT/mTOR pathway inhibition in PLA2R-activated podocytes help protect podocytes from apoptosis. The therapeutic potential of rapamycin shown in this study provides cellular evidence supporting the repurposing of rapamycin for MN treatment. CI - Copyright (c) 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved. FAU - Chiou, Terry Ting-Yu AU - Chiou TT AD - Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan. Electronic address: cyang@cgmh.org.tw. FAU - Chau, You-Ying AU - Chau YY AD - Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK. Electronic address: You-Ying.Chau@ed.ac.uk. FAU - Chen, Jin-Bor AU - Chen JB AD - Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. Electronic address: jbchen@cgmh.org.tw. FAU - Hsu, Hsiang-Hao AU - Hsu HH AD - Kidney Research Center, Department of Nephrology, Linkou Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan; College of Medicine, School of Medicine, Chang Gung University, Taoyuan 33302, Taiwan. Electronic address: hsianghao@cgmh.org.tw. FAU - Hung, Shao-Pei AU - Hung SP AD - Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. Electronic address: helenhung@cgmh.org.tw. FAU - Lee, Wen-Chin AU - Lee WC AD - Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. Electronic address: leewc@cgmh.org.tw. LA - eng PT - Journal Article DEP - 20211023 PL - France TA - Biomed Pharmacother JT - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JID - 8213295 RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (MTOR Inhibitors) RN - 0 (PLA2R1 protein, human) RN - 0 (Receptors, Phospholipase A2) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Apoptosis/*drug effects MH - Apoptosis Regulatory Proteins/metabolism MH - Cell Line MH - Enzyme Activation MH - Glomerulonephritis, Membranous/*drug therapy/enzymology/pathology MH - Humans MH - MTOR Inhibitors/*pharmacology MH - Phosphatidylinositol 3-Kinase/*metabolism MH - Podocytes/*drug effects/enzymology/pathology MH - Proto-Oncogene Proteins c-akt/*metabolism MH - Receptors, Phospholipase A2/*metabolism MH - Signal Transduction MH - Sirolimus/*pharmacology MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism OTO - NOTNLM OT - Mammalian target of rapamycin OT - Membranous nephropathy OT - Phospholipase A2 receptor OT - Podocyte EDAT- 2021/10/27 06:00 MHDA- 2022/01/27 06:00 CRDT- 2021/10/26 20:26 PHST- 2021/07/27 00:00 [received] PHST- 2021/10/11 00:00 [revised] PHST- 2021/10/19 00:00 [accepted] PHST- 2021/10/27 06:00 [pubmed] PHST- 2022/01/27 06:00 [medline] PHST- 2021/10/26 20:26 [entrez] AID - S0753-3322(21)01133-1 [pii] AID - 10.1016/j.biopha.2021.112349 [doi] PST - ppublish SO - Biomed Pharmacother. 2021 Dec;144:112349. doi: 10.1016/j.biopha.2021.112349. Epub 2021 Oct 23.