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

Autor: Shao-Pei Hung, Wen-Chin Lee, Hsiang-Hao Hsu, Jin-Bor Chen, You-Ying Chau, Terry Ting-Yu Chiou
Rok vydání: 2021
Předmět:
Membranous nephropathy
Apoptosis Regulatory Proteins/metabolism
Phospholipase A2 receptor
Podocyte
Apoptosis
RM1-950
Glomerulonephritis
Membranous
Cell Line
chemistry.chemical_compound
Downregulation and upregulation
Proto-Oncogene Proteins c-akt/metabolism
medicine
Humans
LY294002
Protein kinase B
PI3K/AKT/mTOR pathway
Sirolimus
MTOR Inhibitors/pharmacology
Pharmacology
TOR Serine-Threonine Kinases/antagonists & inhibitors
Mammalian target of rapamycin
biology
Podocytes
Chemistry
Receptors
Phospholipase A2
TOR Serine-Threonine Kinases
Cytochrome c
Apoptosis/drug effects
Sirolimus/pharmacology
MTOR Inhibitors
General Medicine
Enzyme Activation
Crosstalk (biology)
Receptors
Phospholipase A2/metabolism
medicine.anatomical_structure
Cancer research
biology.protein
Therapeutics. Pharmacology
Phosphatidylinositol 3-Kinase
Podocytes/drug effects
Apoptosis Regulatory Proteins
Proto-Oncogene Proteins c-akt
Phosphatidylinositol 3-Kinase/metabolism
Glomerulonephritis
Membranous/drug therapy
Signal Transduction
Zdroj: Biomedicine & Pharmacotherapy, Vol 144, Iss, Pp 112349-(2021)
Chioua, T T-Y, Chau, Y-Y, Chen, J-B, Hsu, H-H, Huang, S-P & Lee, W-C 2021, ' Rapamycin attenuates PLA2R activation-mediated podocyte apoptosis via the PI3K/AKT/mTOR pathway ', Biomedicine and Pharmacotherapy, vol. 144 . https://doi.org/10.1016/j.biopha.2021.112349
ISSN: 0753-3322
DOI: 10.1016/j.biopha.2021.112349
Popis: 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.
Databáze: OpenAIRE
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