Exosome miR-30a-5p Regulates Glomerular Endothelial Cells' EndMT and Angiogenesis by Modulating Notch1/VEGF Signaling Pathway. 2024

Yaxian Ning, and Xiaochun Zhou, and Gouqin Wang, and Lili Zhang, and Jianqin Wang
Department of Nephrology, Second Hospital of Lanzhou University, Lanzhou 730030, Gansu, China.

BACKGROUND Diabetic nephropathy (DN) is one of the microvascular complications of diabetes. Endothelial-mesenchymal transition (EndMT) and endothelial damage lead to abnormal angiogenesis in DN. OBJECTIVE This study aimed to investigate the role of exosome miR-30a-5p in high glucose (HG)-induced glomerular endothelial cells (GECs) dysfunction and explore the underlying mechanisms. METHODS GECs were cultured in normal glucose (5.5 mM) and HG (30 mM) conditions. The recipient GECs were transfected with exosome or miR-30a-5p mimic/inhibitor and then detected by using CCK-8 and flow cytometry assay. Luciferase analysis was used to verify miR-30a-5p acted on notch homolog protein 1 (Notch1). RT-qPCR and Western blot were used to detect the expression of VE-cadherin, α-SMA, vascular endothelial growth factor (VEGF) and Notch1. In vivo, exosome miR-30a-5p was administered to DN mice, and periodic acid-Schiff (PAS) staining, UTP levels, and HbA1c levels were measured. RESULTS The expression of miR-30a-5p was downregulated in HG-treated GECs. Exosome miR-30a-5p significantly promoted cell proliferation, and migration and reduced apoptosis of GECs under HG conditions. MiR-30a-5p directly targeted the 3-UTR region of Notch1. Exosome miR-30a-5p reduced the expression levels of Notch1 and VEGF, both at mRNA and protein levels. Furthermore, exosome miR-30a-5p inhibited HG-induced EndMT, as evidenced by increased VE-cadherin and reduced α-SMA. In vivo studies demonstrated that exosome miR-30a-5p reduced serum HbA1c levels and 24-hour urine protein quantification. CONCLUSIONS This study provides evidence that exosome miR-30a-5p suppresses EndMT and abnormal angiogenesis of GECs by modulating the Notch1/VEGF signaling pathway. These findings suggest that exosome miR-30a-5p could be a potential therapeutic strategy for the treatment of DN.

UI MeSH Term Description Entries
D003928 Diabetic Nephropathies KIDNEY injuries associated with diabetes mellitus and affecting KIDNEY GLOMERULUS; ARTERIOLES; KIDNEY TUBULES; and the interstitium. Clinical signs include persistent PROTEINURIA, from microalbuminuria progressing to ALBUMINURIA of greater than 300 mg/24 h, leading to reduced GLOMERULAR FILTRATION RATE and END-STAGE RENAL DISEASE. Diabetic Glomerulosclerosis,Glomerulosclerosis, Diabetic,Diabetic Kidney Disease,Diabetic Nephropathy,Intracapillary Glomerulosclerosis,Kimmelstiel-Wilson Disease,Kimmelstiel-Wilson Syndrome,Nodular Glomerulosclerosis,Diabetic Kidney Diseases,Glomerulosclerosis, Nodular,Kidney Disease, Diabetic,Kidney Diseases, Diabetic,Kimmelstiel Wilson Disease,Kimmelstiel Wilson Syndrome,Nephropathies, Diabetic,Nephropathy, Diabetic,Syndrome, Kimmelstiel-Wilson
D005947 Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Dextrose,Anhydrous Dextrose,D-Glucose,Glucose Monohydrate,Glucose, (DL)-Isomer,Glucose, (alpha-D)-Isomer,Glucose, (beta-D)-Isomer,D Glucose,Dextrose, Anhydrous,Monohydrate, Glucose
D006442 Glycated Hemoglobin Products of non-enzymatic reactions between GLUCOSE and HEMOGLOBIN (occurring as a minor fraction of the hemoglobin of ERYTHROCYTES.) It generally refers to glycated HEMOGLOBIN A. Hemoglobin A1c (Hb A1c) is hemoglobin A with GLYCATION on a terminal VALINE of the beta chain. Glycated hemoglobin A is used as an index of the average blood sugar level over a lifetime of erythrocytes. Fructated Hemoglobins,Glycohemoglobin,Glycohemoglobin A,Glycohemoglobins,Glycosylated Hemoglobin A,Hb A1c,HbA1,Hemoglobin A(1),Hemoglobin A, Glycosylated,Glycated Hemoglobin A,Glycated Hemoglobin A1c,Glycated Hemoglobins,Glycosylated Hemoglobin A1c,Hb A1,Hb A1a+b,Hb A1a-1,Hb A1a-2,Hb A1b,Hemoglobin, Glycated A1a-2,Hemoglobin, Glycated A1b,Hemoglobin, Glycosylated,Hemoglobin, Glycosylated A1a-1,Hemoglobin, Glycosylated A1b,A1a-1 Hemoglobin, Glycosylated,A1a-2 Hemoglobin, Glycated,A1b Hemoglobin, Glycated,A1b Hemoglobin, Glycosylated,Glycated A1a-2 Hemoglobin,Glycated A1b Hemoglobin,Glycosylated A1a-1 Hemoglobin,Glycosylated A1b Hemoglobin,Glycosylated Hemoglobin,Hemoglobin A, Glycated,Hemoglobin A1c, Glycated,Hemoglobin A1c, Glycosylated,Hemoglobin, Glycated,Hemoglobin, Glycated A1a 2,Hemoglobin, Glycosylated A1a 1,Hemoglobins, Fructated,Hemoglobins, Glycated
D000096382 Endothelial-Mesenchymal Transition Phenotypic changes of ENDOTHELIAL CELLS to MESENCHYME type during development or during disease states such as INFLAMMATION; CANCER; FIBROSIS or CARDIOVASCULAR DISEASE. EndMT,Endothelial-Mesenchymal Transformation,Endothelial Mesenchymal Transformation,Endothelial Mesenchymal Transition,Transformation, Endothelial-Mesenchymal,Transition, Endothelial-Mesenchymal
D000096482 Angiogenesis Formation of new blood vessels, which is controlled by chemical signals in the body, such as VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF). This process involves the migration, growth, and differentiation of ENDOTHELIAL CELLS, which line the inside wall of blood vessels. Angiogeneses
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D042461 Vascular Endothelial Growth Factor A The original member of the family of endothelial cell growth factors referred to as VASCULAR ENDOTHELIAL GROWTH FACTORS. Vascular endothelial growth factor-A was originally isolated from tumor cells and referred to as "tumor angiogenesis factor" and "vascular permeability factor". Although expressed at high levels in certain tumor-derived cells it is produced by a wide variety of cell types. In addition to stimulating vascular growth and vascular permeability it may play a role in stimulating VASODILATION via NITRIC OXIDE-dependent pathways. Alternative splicing of the mRNA for vascular endothelial growth factor A results in several isoforms of the protein being produced. Vascular Endothelial Growth Factor,Vascular Endothelial Growth Factor-A,GD-VEGF,Glioma-Derived Vascular Endothelial Cell Growth Factor,VEGF,VEGF-A,Vascular Permeability Factor,Vasculotropin,Glioma Derived Vascular Endothelial Cell Growth Factor,Permeability Factor, Vascular
D042783 Endothelial Cells Highly specialized EPITHELIAL CELLS that line the HEART; BLOOD VESSELS; and lymph vessels, forming the ENDOTHELIUM. They are polygonal in shape and joined together by TIGHT JUNCTIONS. The tight junctions allow for variable permeability to specific macromolecules that are transported across the endothelial layer. Capillary Endothelial Cells,Lymphatic Endothelial Cells,Vascular Endothelial Cells,Capillary Endothelial Cell,Cell, Capillary Endothelial,Cell, Endothelial,Cell, Lymphatic Endothelial,Cell, Vascular Endothelial,Cells, Capillary Endothelial,Cells, Endothelial,Cells, Lymphatic Endothelial,Cells, Vascular Endothelial,Endothelial Cell,Endothelial Cell, Capillary,Endothelial Cell, Lymphatic,Endothelial Cell, Vascular,Endothelial Cells, Capillary,Endothelial Cells, Lymphatic,Endothelial Cells, Vascular,Lymphatic Endothelial Cell,Vascular Endothelial Cell
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus

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