Journal Article

ADAM17 up-regulation in renal transplant dysfunction and non-transplant-related renal fibrosis

Gemma M. Mulder, Wynand B.W.H. Melenhorst, Johanna W.A.M. Celie, Niels J. Kloosterhuis, Jan-Luuk Hillebrands, Rutger J. Ploeg, Marc A. Seelen, Lydia Visser, Marcory C.R.F. van Dijk and Harry van Goor

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 27, issue 5, pages 2114-2122
Published in print May 2012 | ISSN: 0931-0509
Published online October 2011 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfr583
ADAM17 up-regulation in renal transplant dysfunction and non-transplant-related renal fibrosis

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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.

Keywords: ADAM17; EGF receptor; fibrosis; IF/TA; ischaemia–reperfusion injury

Journal Article.  5063 words.  Illustrated.

Subjects: Nephrology

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