Endothelial ADAM17 expression in the progression of kidney injury in an obese mouse model of pre-diabetes

Palau González, Vanesa; Jarrín, Josué; Villanueva, Sofia; Benito, David; Márquez, Eva; Rodríguez, Eva; Soler, María José; Oliveras, Anna; Gimeno, Javier; Sans Atxer, Laia; Crespo Barrio, Marta; Pascual, Julio (Pascual Santos); Barrios Barrera, Clara; Riera Oliva, Marta

doi:http://dx.doi.org/10.3390/ijms23010221

Endothelial ADAM17 expression in the progression of kidney injury in an obese mouse model of pre-diabetes

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Palau V, Jarrín J, Villanueva S, Benito D, Márquez E, Rodríguez E, Soler MJ, Oliveras A, Gimeno J, Sans L, Crespo M, Pascual J, Barrios C, Riera M. Endothelial ADAM17 expression in the progression of kidney injury in an obese mouse model of pre-diabetes. Int J Mol Sci. 2021 Dec 25;23(1):221. DOI: 10.3390/ijms23010221

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.