Rapamycin attenuates PLA2R activation-mediated podocyte apoptosis via the PI3K/AKT/mTOR pathway

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...

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Autores principales:	Terry Ting-Yu Chiou, You-Ying Chau, Jin-Bor Chen, Hsiang-Hao Hsu, Shao-Pei Hung, Wen-Chin Lee
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Membranous nephropathy Phospholipase A2 receptor Mammalian target of rapamycin Podocyte Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/6483ea9e50d64b349c7b6ac6dac6e2ab
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spelling	oai:doaj.org-article:6483ea9e50d64b349c7b6ac6dac6e2ab2021-11-14T04:30:11ZRapamycin attenuates PLA2R activation-mediated podocyte apoptosis via the PI3K/AKT/mTOR pathway0753-332210.1016/j.biopha.2021.112349https://doaj.org/article/6483ea9e50d64b349c7b6ac6dac6e2ab2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0753332221011331https://doaj.org/toc/0753-3322Membranous 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.Terry Ting-Yu ChiouYou-Ying ChauJin-Bor ChenHsiang-Hao HsuShao-Pei HungWen-Chin LeeElsevierarticleMembranous nephropathyPhospholipase A2 receptorMammalian target of rapamycinPodocyteTherapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 144, Iss , Pp 112349- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Membranous nephropathy Phospholipase A2 receptor Mammalian target of rapamycin Podocyte Therapeutics. Pharmacology RM1-950
spellingShingle	Membranous nephropathy Phospholipase A2 receptor Mammalian target of rapamycin Podocyte Therapeutics. Pharmacology RM1-950 Terry Ting-Yu Chiou You-Ying Chau Jin-Bor Chen Hsiang-Hao Hsu Shao-Pei Hung Wen-Chin Lee Rapamycin attenuates PLA2R activation-mediated podocyte apoptosis via the PI3K/AKT/mTOR pathway
description	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.
format	article
author	Terry Ting-Yu Chiou You-Ying Chau Jin-Bor Chen Hsiang-Hao Hsu Shao-Pei Hung Wen-Chin Lee
author_facet	Terry Ting-Yu Chiou You-Ying Chau Jin-Bor Chen Hsiang-Hao Hsu Shao-Pei Hung Wen-Chin Lee
author_sort	Terry Ting-Yu Chiou
title	Rapamycin attenuates PLA2R activation-mediated podocyte apoptosis via the PI3K/AKT/mTOR pathway
title_short	Rapamycin attenuates PLA2R activation-mediated podocyte apoptosis via the PI3K/AKT/mTOR pathway
title_full	Rapamycin attenuates PLA2R activation-mediated podocyte apoptosis via the PI3K/AKT/mTOR pathway
title_fullStr	Rapamycin attenuates PLA2R activation-mediated podocyte apoptosis via the PI3K/AKT/mTOR pathway
title_full_unstemmed	Rapamycin attenuates PLA2R activation-mediated podocyte apoptosis via the PI3K/AKT/mTOR pathway
title_sort	rapamycin attenuates pla2r activation-mediated podocyte apoptosis via the pi3k/akt/mtor pathway
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/6483ea9e50d64b349c7b6ac6dac6e2ab
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Rapamycin attenuates PLA2R activation-mediated podocyte apoptosis via the PI3K/AKT/mTOR pathway

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