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NDT Advance Access published online on May 22, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfp214
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© The Author [2009]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


IL-1RI deficiency ameliorates early experimental renal interstitial fibrosis

Lynelle K. Jones1, Kim M. O’Sullivan1, Timothy Semple1, Michael P. Kuligowski1, Kei Fukami2, Frank Y. Ma3, David J. Nikolic-Paterson1,3, Stephen R. Holdsworth1,3 and A. Richard Kitching1,3,4

1 Department of Medicine, Centre for Inflammatory Diseases, Monash University, Monash Medical Centre, Clayton 2 Vascular Division, The Baker Heart Research Institute, Danielle Alberti Memorial Centre for Diabetes Complications, Melbourne 3 Department of Nephrology 4 Department of Paediatric Nephrology, Monash Medical Centre, Clayton, Victoria, Australia

Correspondence and offprint requests to: A. Richard Kitching; E-mail: richard.kitching{at}med.monash.edu.au



  Abstract

Background. IL-1β has the potential to promote progressive renal disease by effects on macrophage recruitment and activation or by effects mediated through tubular cell transforming growth factor (TGF)-β production, previously demonstrated in vitro.

Methods. The in vivo roles of endogenous IL-1β and its type I receptor (IL-1RI) in renal fibrosis were studied using wild-type C57BL/6 mice, IL-1β–/– and IL-1RI–/– mice with unilateral ureteric obstruction.

Results. After 7 days, IL-1RI–/– mice (IL-1{alpha} and IL-1β deficient) were protected from injury and collagen accumulation. IL-1β–/– mice demonstrated some histological protection, but no reduction in {alpha}1(1) procollagen mRNA or biochemically measured collagen accumulation. Compared with obstructed kidneys from wild-type mice, TGF-β1 mRNA was reduced in IL-1RI–/– mice (with trends to reduced TGF-β2 and TGF-β3). Expression of a downstream TGF-β effector, connective tissue growth factor, was decreased in IL-1RI–/– mice. IL-1RI–/– mice exhibited less tubulointerstitial apoptosis compared with wild-type mice. Macrophage infiltration and adhesion molecule mRNA expression was unchanged in IL-1β–/– or IL-1RI–/– mice. While TNF expression was similar to wild-type mice, IFN-{gamma} expression was reduced in both IL-1β–/– and IL-1RI–/– mice. IL-1RI–/– mice at 14 days showed a catch-up in fibrosis compared with wild-type mice.

Conclusion. IL-1/IL-1RI interactions are profibrotic in renal fibrosis. IL-1RI–/– mice were more protected at an early stage, associated with changes in TGF-β and downstream mediators of fibrosis, but independent of the presence of infiltrating macrophages.

Keywords: IL-1; interstitial fibrosis; macrophages; obstructive uropathy; TGF-β

Received for publication: 7. 1.09
Accepted in revised form: 20. 4.09


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