a6b4e811b3e9baea3de2acd0e49a4675 pmc_35008648.pdf d9291a81908045b541c9a70c19ce75637750a759 pmc_35008648.pdf e66433017da2491f5db45568256d0073cf2bf98dff5645b31e1ae003b657e420 pmc_35008648.pdf Title: Endothelial ADAM17 Expression in the Progression of Kidney Injury in an Obese Mouse Model of Pre-Diabetes Subject: Disintegrin and metalloproteinase domain 17 (ADAM17) activates inflammatory and fibrotic processes through the shedding of various molecules such as Tumor Necrosis Factor- (TNF-) or Transforming Growht Factor- (TGF-). There is a well-recognised link between TNF-, 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. Keywords: ADAM17; obesity; pre-diabetes; endothelial cells Author: Vanesa Palau, Josué Jarrín, Sofia Villanueva, David Benito, Eva Márquez, Eva Rodríguez, María José Soler, Anna Oliveras, Javier Gimeno, Laia Sans, Marta Crespo, Julio Pascual, Clara Barrios and Marta Riera Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Dec 28 09:36:43 2021 CET ModDate: Tue Dec 28 09:48:55 2021 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 12 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 3131382 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- ZKUUEY+VnURWPalladioL Type 1 Custom yes yes no 10 0 VVSYYB+EURM10 Type 1 Builtin yes yes no 15 0 UACKWU+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 IDIURS+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 EPYZVE+URWPalladioL-Ital Type 1 Custom yes yes no 28 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Objects: 586 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Endothelial Adam17 Deletion Modifies Blood Glucose Levels and Renal Function in Obese Mice Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Glucose Tolerance was Modulated by Adam17 Deletion in Endothelial Cells Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Adam17 Deletion in Endothelial Cells Protects Obese Mice from Glomerular Alterations Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Endothelial Adam17 Promotes Renal Macrophage Infiltration in Obese Mice Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Renal Galectin-3 Expression Is Modified by Endothelial Adam17 Deletion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Children: Item: Title: Animal Experiments Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Glucose Tolerance Test Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Urinary Albumin-to-Creatinine Ratio Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Immunohistochemistry on Paraffined-Embedded Tissue Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Western Blot Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Statistical Analyses Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Info: Title: Endothelial ADAM17 Expression in the Progression of Kidney Injury in an Obese Mouse Model of Pre-Diabetes Author: Vanesa Palau, Josué Jarrín, Sofia Villanueva, David Benito, Eva Márquez, Eva Rodríguez, María José Soler, Anna Oliveras, Javier Gimeno, Laia Sans, Marta Crespo, Julio Pascual, Clara Barrios and Marta Riera Subject: Disintegrin and metalloproteinase domain 17 (ADAM17) activates inflammatory and fibrotic processes through the shedding of various molecules such as Tumor Necrosis Factor- (TNF-) or Transforming Growht Factor- (TGF-). There is a well-recognised link between TNF-, 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. 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