Endothelial ADAM17 Expression in the Progression of Kidney Injury in an Obese Mouse Model of Pre-Diabetes

Abstract

Disintegrin and metalloproteinase domain 17 (ADAM17) activates inflammatory and fibrotic processes through the shedding of various molecules such as Tumor Necrosis Factor-α (TNF-α) or Transforming Growht Factor-α (TGF-α). There is a well-recognised link between TNF-α, obesity, inflammation, and diabetes. In physiological situations, ADAM17 is expressed mainly in the distal tubular cell while, in renal damage, its expression increases throughout the kidney including the endothelium. The aim of this study was to characterize, for the first time, an experimental mouse model fed a high-fat diet (HFD) with a specific deletion of Adam17 in endothelial cells and to analyse the effects on different renal structures. Endothelial Adam17 knockout male mice and their controls were fed a high-fat diet, to induce obesity, or standard rodent chow, for 22 weeks. Glucose tolerance, urinary albumin-to-creatinine ratio, renal histology, macrophage infiltration, and galectin-3 levels were evaluated. Results showed that obese mice presented higher blood glucose levels, dysregulated glucose homeostasis, and higher body weight compared to control mice. In addition, obese wild-type mice presented an increased albumin-to-creatinine ratio; greater glomerular size and mesangial matrix expansion; and tubular fibrosis with increased galectin-3 expression. Adam17 deletion decreased the albumin-to-creatinine ratio, glomerular mesangial index, and tubular galectin-3 expression. Moreover, macrophage infiltration in the glomeruli of obese Adam17 knockout mice was reduced as compared to obese wild-type mice. In conclusion, the expression of ADAM17 in endothelial cells impacted renal inflammation, modulating the renal function and histology in an obese pre-diabetic mouse model.

The miR-214-5p/Lactoferrin/miR-224-5p/ADAM17 Axis Is Involved in Goat Mammary Epithelial Cells’ Immune Regulation

“…Of note, the ADAM17 gene was one of the candidate target genes for miR-224-5p and may be related to immune regulation. ADAM17 played an important role in the regulation of inflammation, which was supported by previous findings showing that ADAM17 expression in endothelial cells affected renal inflammation and modulated renal function and histology in an obese prediabetic mouse model [ 31 ]. Furthermore, miR-224 can inhibit the growth and invasion of oral squamous cell carcinoma (OSCC) cells by targeting ADAM17 expression [ 32 ].…”

Diabetic Endothelial Cell Glycogen Synthase Kinase 3β Activation Induces VCAM1 Ectodomain Shedding

“…Dysregulated ADAM activity can increase sCAM ectodomain shedding, contributing to endothelial dysfunction and the recruitment of inflammatory cells in diabetic vasculature [ 52 ]. In diabetic retinopathy, the ADAM17-mediated cleavage of CX3CL1 and VCAM-1 in retinal endothelial cells has been associated with vascular leakage and retinal neovascularization [ 53 ]. Moreover, the ADAM10-mediated shedding of CX3CL1 has been linked to diabetic nephropathy, where increased levels of soluble CX3CL1 contribute to kidney injury and fibrosis [ 54 ].…”