<b>Inhibition of GLUT1 Ameliorates Thickening of the Glomerular Basement Membrane via the Rheb/mTORC1 Pathway in Diabetic Nephropathy</b>

作者：Jitu Xu, Jiaoyu Shi, Ping Hu, Nan Jiang, Jiayan Zhong, Guangze Shao, Siqi Zhu, Yue Gu, Wenlu Jia, Guozhe Cheng, Xitong Xu, Junying Liu, Zhonghua Zhao, Zhigang Zhang, Shuyang Wang, Jun Liu, Jian-Jun Liu, Haidong He, Huijuan Wu · 年份：2026 · DOI：10.2337/figshare.32204640 · 研究领域：Chronic Kidney Disease and Diabetes、Renal Diseases and Glomerulopathies、Metabolism, Diabetes, and Cancer

<p dir="ltr">Thickening of the glomerular basement membrane (GBM) is one of the most common pathological changes in diabetic nephropathy (DN), but its underlying mechanisms remain unclear. Collagen IV alpha 1 (Col IV α1) is predominantly expressed by endothelial cells and is upregulated in the glomeruli of diabetic nephropathy. The glucose transporter type 1 (GLUT1) serves as the primary transporter for glucose uptake in endothelial cells. This study demonstrates that GLUT1 and Col IV α1 expression are both upregulated and positively correlated in glomerular endothelial cells (GECs) of diabetic nephropathy. Inhibition of GLUT1 improved renal dysfunction and morphological abnormalities associated with diabetic nephropathy progression in db/db diabetic mice and streptozotocin (STZ)-induced diabetic rat models. Mechanistically, GLUT1 promotes Col IV α1 overexpression through activation of the Rheb/mTORC1 pathway in GECs. In vitro studies revealed that O-GlcNAcylation of Rheb appears to mediate GLUT1-driven Rheb upregulation and subsequent mTORC1 activation. Collectively, these data establish the GLUT1-Rheb/mTORC1-Col IV α1 axis in GECs, highlighting the pivotal role of glomerular endothelial cells in mediating GBM thickening during diabetic nephropathy pathogenesis.</p>