NDT Advance Access originally published online on April 2, 2008
Nephrology Dialysis Transplantation 2008 23(8):2480-2491; doi:10.1093/ndt/gfn140
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Patterns of interstitial inflammation during the evolution of renal injury in experimental aristolochic acid nephropathy
1 Unit of Experimental Nephrology, Faculty of Medicine 2 Nephrology 3 Pathology Departments, Erasme Hospital 4 Laboratory of Toxicology, Institute of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium 5 INSERM U785, Lavoisier Building, Paul Brousse Hospital, Paris, France
Correspondence and offprint requests to: Joëlle L. Nortier, Department of Nephrology, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, B-1070 Brussels, Belgium. Tel: +32-2-555-3334; Fax: +32-2-555-6499; E-mail: jnortier{at}ulb.ac.be
 |
Abstract |
|---|
Background. Interstitial inflammation is a prominent feature associated with the severity of renal injury and progressive kidney failure. We utilized an animal model of aristolochic acid (AA)-induced nephropathy (AAN) to assess patterns of infiltration and inflammation during the evolution of tubulointerstitial damage and to relate them to the development of fibrosis.
Methods. Male Wistar rats receiving sc daily AA or vehicle were sacrificed between Days 1 and 35. Infiltrating mononuclear cells were characterized by immunohistochemistry. The kidney infiltrating T lymphocytes were phenotyped by flow cytometry. Urinary levels of Th-1/ Th-2 cytokines, of monocyte chemoattractant protein-1 and of active transforming growth factor-beta (TGF-β) were measured. Tissue expression of phosphorylated smad 2/3 protein was used to examine the TGF-β signalling pathway.
Results. In AA rats, monocytes/macrophages and T lymphocytes predominantly infiltrated areas of necrotic proximal tubular cells. The coexpressions of ED1 and/or Ki-67/MHCII by infiltrating cells reflected monocyte/macrophage proliferation and their activation, respectively. The accumulation of cytotoxic T lymphocytes was attested by severe signs of CD8+ cell tubulitis. The CD8/E-cadherin costaining confirmed intrarenal homing of CD8+CD103+ cells. Urinary levels of proinflammatory cytokines and of active TGF-β significantly increased at Days 10 and 35. An early and persistent nuclear overexpression of phosphorylated smad 2/3 protein was detected in tubular and interstitial compartments.
Conclusion. An early and massive interstitial inflammation characterized by activated monocytes/macrophages and cytotoxic CD8+CD103+ T lymphocytes is demonstrated for the first time during the progression of experimental AAN. The involvement in an interstitial fibrosis onset of active TGF-β is highly suggested, at least via the psmad2/3 intracellular signalling pathway.
Keywords: aristolochic acid; macrophages; renal fibrosis; T lymphocytes; transforming growth factor-β
* A.P. is a research fellow in Nephrology of the Université Libre de Bruxelles (Brussels, Belgium).
C.D. is a senior research associate with the Belgian Research Found for Fundamental Research (FNRS, Belgium).
Received for publication: 13. 9.07
Accepted in revised form: 20. 2.08