c84b7c9adce89aaae25b6e7718620cd2 pmc_34884897.pdf bf8d890b06ef18387aec83403405a773b97fc4c5 pmc_34884897.pdf 51176024a837ef249780b087e17f97f45e5521fb27cf681f2d524a37444ab7d8 pmc_34884897.pdf Title: Redefining the Role of ADAM17 in Renal Proximal Tubular Cells and Its Implications in an Obese Mouse Model of Pre-Diabetes Subject: Acute and chronic kidney lesions induce an increase in A Disintegrin And Metalloproteinase domain 17 (ADAM17) that cleaves several transmembrane proteins related to inflammatory and fibrotic pathways. Our group has demonstrated that renal ADAM17 is upregulated in diabetic mice and its inhibition decreases renal inflammation and fibrosis. The purpose of the present study was to analyze how Adam17 deletion in proximal tubules affects different renal structures in an obese mice model. Tubular Adam17 knockout male mice and their controls were fed a high-fat diet (HFD) for 22 weeks. Glucose tolerance, urinary albumin-to-creatinine ratio, renal histology, and pro-inflammatory and pro-fibrotic markers were evaluated. Results showed that wild-type mice fed an HFD became obese with glucose intolerance and renal histological alterations mimicking a pre-diabetic condition; consequently, greater glomerular size and mesangial expansion were observed. Adam17 tubular deletion improved glucose tolerance and protected animals against glomerular injury and prevented podocyte loss in HFD mice. In addition, HFD mice showed more glomerular macrophages and collagen accumulation, which was prevented by Adam17 deletion. Galectin-3 expression increased in the proximal tubules and glomeruli of HFD mice and ameliorated with Adam17 deletion. In conclusion, Adam17 in proximal tubules influences glucose tolerance and participates in the kidney injury in an obese pre-diabetic murine model. The role of ADAM17 in the tubule impacts on glomerular inflammation and fibrosis. Keywords: ADAM17; obesity; pre-diabetes; renal proximal tubular cells Author: Vanesa Palau, Sofia Villanueva, Josué Jarrín, 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: Fri Dec 3 12:32:37 2021 CET ModDate: Fri Dec 3 12:36:38 2021 CET Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 15 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 3605521 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- AWHDWW+VnURWPalladioL Type 1 Custom yes yes no 10 0 YFFQBZ+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 NCERPP+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 IZHROT+URWPalladioL-Roma Type 1 Custom yes yes 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TrueType WinAnsi yes yes no 323 0 PLHDMI+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 419 0 PLHDMK+PalatinoLinotype TrueType WinAnsi yes yes no 422 0 PLHDMM+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 425 0 PLIDNM+Calibri,Bold CID TrueType Identity-H yes yes yes 428 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-10-02 03:37:58 CEST RepresentationInformation: pmc_34884897.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2023-03-31 12:06:28 CEST Size: 3605521 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 688 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Children: Item: Title: Tubular Adam17 Deletion Modifies Blood Glucose Levels and Renal Function in Obese Mice Destination: subsection.2.1 Item: Title: Glucose Homeostasis Is Influenced by Tubular Adam17 Deletion Destination: subsection.2.2 Item: Title: Renal Histology Is Modified in Obese Tubular Adam17 Knockout Mice Destination: subsection.2.3 Item: Title: Adam17 Deletion Modulates Renal Inflammation Destination: subsection.2.4 Item: Title: Renal Fibrosis Changes with Adam17 Deletion Destination: subsection.2.5 Item: Title: Oxidative Stress Induction in the Obese Model with Tubular Adam17 Deletion Destination: subsection.2.6 Item: Title: Discussion Destination: section.3 Item: Title: Materials and Methods Destination: section.4 Children: Item: Title: Animal Experiments Destination: subsection.4.1 Item: Title: Glucose Tolerance Test Destination: subsection.4.2 Item: Title: Urine Albumin Creatinine Ratio Destination: subsection.4.3 Item: Title: Immunohistochemistry on Paraffined-Embedded Tissue Destination: subsection.4.4 Item: Title: Western Blot Destination: subsection.4.5 Item: Title: Gene Expression Destination: subsection.4.6 Item: Title: Statistical Analyses Destination: subsection.4.7 Item: Title: References Destination: subsection.4.7 Info: Title: Redefining the Role of ADAM17 in Renal Proximal Tubular Cells and Its Implications in an Obese Mouse Model of Pre-Diabetes Author: Vanesa Palau, Sofia Villanueva, Josué Jarrín, 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: Acute and chronic kidney lesions induce an increase in A Disintegrin And Metalloproteinase domain 17 (ADAM17) that cleaves several transmembrane proteins related to inflammatory and fibrotic pathways. Our group has demonstrated that renal ADAM17 is upregulated in diabetic mice and its inhibition decreases renal inflammation and fibrosis. The purpose of the present study was to analyze how Adam17 deletion in proximal tubules affects different renal structures in an obese mice model. Tubular Adam17 knockout male mice and their controls were fed a high-fat diet (HFD) for 22 weeks. Glucose tolerance, urinary albumin-to-creatinine ratio, renal histology, and pro-inflammatory and pro-fibrotic markers were evaluated. Results showed that wild-type mice fed an HFD became obese with glucose intolerance and renal histological alterations mimicking a pre-diabetic condition; consequently, greater glomerular size and mesangial expansion were observed. Adam17 tubular deletion improved glucose tolerance and protected animals against glomerular injury and prevented podocyte loss in HFD mice. In addition, HFD mice showed more glomerular macrophages and collagen accumulation, which was prevented by Adam17 deletion. Galectin-3 expression increased in the proximal tubules and glomeruli of HFD mice and ameliorated with Adam17 deletion. In conclusion, Adam17 in proximal tubules influences glucose tolerance and participates in the kidney injury in an obese pre-diabetic murine model. The role of ADAM17 in the tubule impacts on glomerular inflammation and fibrosis. 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