METTL14 derived from exosomes of M1 macrophages promotes high glucose-induced apoptosis, inflammation and oxidative stress in glomerular endothelial cells by mediating PAQR3 m6A modification.
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引用次数: 0
Abstract
Background: Methyltransferase 14 (METTL14) mediated N6-methyladenine (m6A) RNA methylation and progestin and AdipoQ receptor family member 3 (PAQR3) are reported to be involved in diabetic nephropathy (DN) progression. Here, we explored whether the effects of PAQR3 on DN was associated with METTL14-induced m6A and their relationship with macrophage-related exosomes in DN progression.
Methods: Human glomerular endothelial cells (GECs) were incubated in high glucose (HG) condition to mimic DN condition in vitro. Exosomes were isolated from M1 macrophages and co-cultured with GECs. qRT-PCR and western blotting detected the levels of genes and proteins. Cell functions were determined using cell counting kit-8 assay and flow cytometry. ELISA analysis detected inflammatory factors, and oxidative stress was evaluated by measuring reactive oxygen species and malondialdehyde. The m6A modification profile was determined by methylated RNA immunoprecipitation assay and the interaction was verified by dual-luciferase reporter assay.
Results: HG elevated PAQR3 expression levels in GECs. PAQR3 silencing reversed HG-induced viability arrest, apoptosis, inflammatory response, and oxidative stress. M1 macrophage co-culture could suppress HG-induced GEC injury. PAQR3 was packaged into M1 macrophage-derived exosomes, and M1 macrophages regulated HG-induced GEC injury by secreting PAQR3 into cells via exosomes. Mechanistically, METTL14 induced PAQR3 m6A modification. METTL14 was enriched in M1 macrophage-derived exosomes. METTL14 knockdown in M1 macrophage-derived exosomes protected GEC from HG-induced viability arrest, apoptosis, inflammation and oxidative stress by regulating PAQR3.
Conclusion: Exosomal METTL14 derived from M1 macrophages promoted HG-induced apoptosis, inflammation and oxidative stress in GECs by mediating PAQR3 m6A modification.
期刊介绍：
Clinical and Experimental Nephrology is a peer-reviewed monthly journal, officially published by the Japanese Society of Nephrology (JSN) to provide an international forum for the discussion of research and issues relating to the study of nephrology. Out of respect for the founders of the JSN, the title of this journal uses the term “nephrology,” a word created and brought into use with the establishment of the JSN (Japanese Journal of Nephrology, Vol. 2, No. 1, 1960). The journal publishes articles on all aspects of nephrology, including basic, experimental, and clinical research, so as to share the latest research findings and ideas not only with members of the JSN, but with all researchers who wish to contribute to a better understanding of recent advances in nephrology. The journal is unique in that it introduces to an international readership original reports from Japan and also the clinical standards discussed and agreed by JSN.
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