The CREB/KMT5A complex regulates PTP1B to modulate high glucose-induced endothelial inflammatory factor levels in diabetic nephropathy
| العنوان: | The CREB/KMT5A complex regulates PTP1B to modulate high glucose-induced endothelial inflammatory factor levels in diabetic nephropathy |
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| المؤلفون: | Xue Li, Minmin Zhu, Ting Huang, Changhong Miao, Fei Wang, Wenting Hou, Lihong Lu |
| المصدر: | Cell Death and Disease, Vol 12, Iss 4, Pp 1-14 (2021) Cell Death & Disease |
| بيانات النشر: | Nature Publishing Group, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, medicine.medical_specialty, Endothelium, Immunology, CREB, Article, Umbilical vein, Histone H4, Diabetic nephropathy, Pathogenesis, 03 medical and health sciences, Cellular and Molecular Neuroscience, Diabetes complications, Internal medicine, medicine, Animals, Humans, Diabetic Nephropathies, lcsh:QH573-671, Cyclic AMP Response Element-Binding Protein, Protein Tyrosine Phosphatase, Non-Receptor Type 1, 030102 biochemistry & molecular biology, biology, Chemistry, lcsh:Cytology, Type 2 diabetes, Cell Biology, Methylation, Middle Aged, medicine.disease, Rats, Glucose, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Hyperglycemia, biology.protein, Phosphorylation, hormones, hormone substitutes, and hormone antagonists |
| الوصف: | Diabetic nephropathy (DN) is the primary microvascular complication of diabetes mellitus and may result in end-stage renal disease. The overproduction of various inflammatory factors is involved in the pathogenesis of DN. Protein tyrosine phosphatase 1B (PTP1B) modulates the expression of a series of cytokines and nuclear factor kappa B (NF-κB) activity. cAMP response element-binding protein (CREB) and lysine methyltransferase 5A (KMT5A) have been reported to participate in the maintenance of a healthy endothelium. In the present study, we hypothesise that CREB associates with KMT5A to modulate PTP1B expression, thus contributing to high glucose-mediated glomerular endothelial inflammation. Our analyses revealed that plasma inflammatory factor levels, glomerular endothelial p65 phosphorylation and PTP1B expression were increased in DN patients and rats. In vitro, high glucose increased endothelial inflammatory factor levels and p65 phosphorylation by augmenting PTP1B expression in human umbilical vein endothelial cells (HUVECs). Moreover, high glucose decreased CREB and KMT5A expression. CREB overexpression and KMT5A overexpression both inhibited high glucose-induced PTP1B expression, p65 phosphorylation and endothelial inflammatory factor levels. si-CREB- and sh-KMT5A-induced p65 phosphorylation and endothelial inflammatory factor levels were reversed by si-PTP1B. Furthermore, CREB was associated with KMT5A. Mechanistic research indicated that CREB and histone H4 lysine 20 methylation (H4K20me1, a downstream target of KMT5A) occupy the PTP1B promoter region. sh-KMT5A augmented PTP1B promoter activity and activated the positive effect of si-CREB on PTP1B promoter activity. Our in vivo study demonstrated that CREB and KMT5A were downregulated in glomerular endothelial cells of DN patients and rats. In conclusion, CREB associates with KMT5A to promote PTP1B expression in vascular endothelial cells, thus contributing to hyperglycemia-induced inflammatory factor levels in DN patients and rats. |
| اللغة: | English |
| تدمد: | 2041-4889 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c159e8de27353c026b316e2d39021bbfTest https://doaj.org/article/4abb9c8e7d2b4e1fba4ee9466da74fa8Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c159e8de27353c026b316e2d39021bbf |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20414889 |
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