| Autor: |
Lai SWT; Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA., Bhattacharya S; Department of Computational and Quantitative Medicine, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA., Lopez Gonzalez EJ; Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA., Shuck SC; Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA. |
| Jazyk: |
angličtina |
| Zdroj: |
Antioxidants (Basel, Switzerland) [Antioxidants (Basel)] 2024 Jan 10; Vol. 13 (1). Date of Electronic Publication: 2024 Jan 10. |
| DOI: |
10.3390/antiox13010085 |
| Abstrakt: |
Diabetic kidney disease (DKD) is a leading cause of death in patients with diabetes. An early precursor to DKD is endothelial cell dysfunction (ECD), which often precedes and exacerbates vascular disease progression. We previously discovered that covalent adducts formed on DNA, RNA, and proteins by the reactive metabolic by-product methylglyoxal (MG) predict DKD risk in patients with type 1 diabetes up to 16 years pre-diagnosis. However, the mechanisms by which MG adducts contribute to vascular disease onset and progression remain unclear. Here, we report that the most predominant MG-induced nucleoside adducts, N 2 -(1-carboxyethyl)-deoxyguanosine (CEdG) and N 2 -(1-carboxyethyl)-guanosine (CEG), drive endothelial dysfunction. Following CEdG or CEG exposure, primary human umbilical vein endothelial cells (HUVECs) undergo endothelial dysfunction, resulting in enhanced monocyte adhesion, increased reactive oxygen species production, endothelial permeability, impaired endothelial homeostasis, and exhibit a dysfunctional transcriptomic signature. These effects were discovered to be mediated through the receptor for advanced glycation end products (RAGE), as an inhibitor for intracellular RAGE signaling diminished these dysfunctional phenotypes. Therefore, we found that not only are MG adducts biomarkers for DKD, but that they may also have a role as potential drivers of vascular disease onset and progression and a new therapeutic modality. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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