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Am J Physiol Renal Physiol 297: F781-F790, 2009. First published June 17, 2009; doi:10.1152/ajprenal.90610.2008
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ADAM17 upregulation in human renal disease: a role in modulating TGF-{alpha} availability?

W. B. Melenhorst,1 L. Visser,1 A. Timmer,1 M. C. van den Heuvel,1 C. A. Stegeman,2 and H. van Goor1

1Department of Pathology and Medical Biology and 2Department of Nephrology, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands

Submitted 15 October 2008 ; accepted in final form 12 June 2009

A disintegrin and metalloproteinase (ADAM)17 sheds growth factors from the cell membrane, including epidermal growth factor receptor (EGFR) ligand transforming growth factor (TGF)-{alpha}. In mice, angiotensin II infusion induces renal fibrosis via ADAM17-mediated TGF-{alpha} shedding and subsequent EGFR activation. Pharmacological ADAM17 inhibition reduced renal fibrotic lesions and improved renal function, positioning ADAM17 as a promising target of intervention in renal disease. We studied ADAM17 expression in the human kidney. ADAM17 mRNA was constitutively expressed in normal adult kidneys, with highest expression in distal tubules. In human renal disease, ADAM17 was de novo expressed in proximal tubules, peritubular capillaries, and glomerular mesangium and upregulated in podocytes. Glomerular mesangial and endothelial ADAM17 were associated with mesangial matrix expansion, focal glomerulosclerosis, and glomerular macrophage infiltration (P < 0.01). Peritubular capillary and proximal tubular ADAM17 were associated with interstitial fibrosis and interstitial macrophage infiltration (P < 0.05). Both glomerular and interstitial ADAM17 were associated with decreased renal function (P < 0.05). In renal fibrosis, ADAM17 colocalized with TGF-{alpha}. Moreover, in cultured human podocytes and proximal tubular cells, pharmacological ADAM17 inhibition reduced constitutive TGF-{alpha} shedding by 78% (P < 0.005) and 100% (P < 0.05), respectively, and phorbol ester-induced TGF-{alpha} shedding by 84% (P < 0.005) and 92% (P = 0.005), respectively. Finally, ADAM17 inhibition reduced cellular proliferation. In conclusion, the ADAM17 expression pattern and its role in shedding TGF-{alpha} from cultured human kidney cells suggest a role in the development of fibrosis. Since EGFR signaling is implicated in renal fibrosis, targeting ADAM17 to reduce availability of EGFR ligand TGF-{alpha} may represent a promising way of intervention in human renal disease.

tumor necrosis factor-{alpha} converting enzyme; kidney; podocyte; proximal tubular cell; fibrosis


Address for reprint requests and other correspondence: W. B. Melenhorst, Univ. Medical Center Groningen, Sector F, Dept. of Pathology and Laboratory Medicine, PO Box 196, 9700 AD Groningen, The Netherlands (e-mail: w.b.w.h.melenhorst{at}path.umcg.nl)






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