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BACKGROUND: Interstitial fibrosis and tubular atrophy (IF/TA) is an important cause of renal function loss and ischaemia-reperfusion (I/R) injury is considered to play an important role in its pathophysiology. The aim of the present study was to investigate the role of a disintegrin and metalloproteinase 17 (ADAM17) in human renal allograft disease and in experimental I/R injury of the kidney. METHODS: We studied the expression of ADAM17 messenger RNA (mRNA) in IF/TA and control kidneys by reverse transcription-polymerase chain reaction and in situ hybridization. Moreover, we assessed ADAM17-mediated heparin-binding epidermal growth factor (HB-EGF) shedding in immortalized human cells. Finally, we studied the effect of pharmacological ADAM17 inhibition in a model of renal I/R injury in rats. RESULTS: ADAM17 mRNA was up-regulated in IF/TA when compared to control kidneys. In normal kidneys, ADAM17 mRNA was weakly expressed in proximal tubules, peritubular capillaries, glomerular endothelium and parietal epithelium. In IF/TA, tubular, capillary and glomerular ADAM17 expression was strongly enhanced with de novo expression in the mesangium. In interstitial fibrotic lesions, we observed co-localization of ADAM17 with HB-EGF protein. In vitro, inhibition of ADAM17 with TNF484 resulted in a dose-dependent reduction of HB-EGF shedding in phorbol 12-myrisate 13-acetate-stimulated cells and non-stimulated cells. In vivo, ADAM17 inhibition significantly reduced the number of glomerular and interstitial macrophages at Day 4 of reperfusion. CONCLUSIONS: In conclusion, HB-EGF co-expresses with ADAM17 in renal interstitial fibrosis, suggesting a potential interaction in IF/TA. Targeting ADAM17 to reduce epidermal growth factor receptor phosphorylation could be a promising way of intervention in human renal disease.

Original publication

DOI

10.1093/ndt/gfr583

Type

Journal article

Journal

Nephrol Dial Transplant

Publication Date

05/2012

Volume

27

Pages

2114 - 2122

Keywords

ADAM Proteins, ADAM17 Protein, Adolescent, Adult, Aged, Aged, 80 and over, Animals, Atrophy, Cells, Cultured, Child, Child, Preschool, Dose-Response Relationship, Drug, Female, Fibrosis, Heparin-binding EGF-like Growth Factor, Humans, Hydroxamic Acids, In Vitro Techniques, Intercellular Signaling Peptides and Proteins, Kidney, Kidney Transplantation, Male, Middle Aged, Models, Animal, RNA, Messenger, Rats, Rats, Wistar, Reperfusion Injury, Up-Regulation, Young Adult