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Am J Physiol Renal Physiol 292: F313-F320, 2007. First published August 8, 2006; doi:10.1152/ajprenal.00180.2006
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Induction of kidney injury molecule-1 in homozygous Ren2 rats is attenuated by blockade of the renin-angiotensin system or p38 MAP kinase

Martin H. de Borst,1 Mirjan M. van Timmeren,1 Vishal S. Vaidya,2 Rudolf A. de Boer,3 Mario B. A. van Dalen,1 Andrea B. Kramer,1 Theo A. Schuurs,4 Joseph V. Bonventre,2 Gerjan Navis,5 and Harry van Goor1

Departments of 1Pathology and Laboratory Medicine, 3Cardiology, 4Surgery, and 5Internal Medicine, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands; and 2Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

Submitted 24 May 2006 ; accepted in final form 1 August 2006

Kidney injury molecule-1 (Kim-1) is associated with ischemic and proteinuric tubular injury; however, whether dysregulation of the renin-angiotensin system (RAS) can also induce Kim-1 is unknown. We studied Kim-1 expression in homozygous Ren2 rats, characterized by renal damage through excessive RAS activation. We also investigated whether antifibrotic treatment (RAS blockade or p38 MAP kinase inhibition) would affect Kim-1 expression. At 7 wk of age, homozygous Ren2 rats received a nonhypotensive dose of candesartan (0.05 mg·kg–1·day–1 sc) or the p38 inhibitor SB-239063 (15 mg·kg–1·day–1 sc) for 4 wk; untreated Ren2 and Sprague-Dawley (SD) rats served as controls. Kim-1 mRNA and protein expression were determined by quantitative PCR and immunohistochemistry, respectively, and related to markers of prefibrotic renal damage. Urinary Kim-1 was measured in 8-wk-old Ren2 and SD rats with and without angiotensin-converting enzyme inhibition (ramipril, 1 mg·kg–1·day–1 in drinking water for 4 wk). Untreated Ren2 rats showed a >20-fold increase in renal Kim-1 mRNA (expressed as Kim-1-to-GAPDH ratio): 75.5 ± 43.6 vs. 3.1 ± 1.0 in SD rats (P < 0.01). Candesartan and SB-239063 strongly reduced Kim-1 mRNA: 3.1 ± 1.5 (P < 0.01) and 9.8 ± 4.2 (P < 0.05), respectively. Kim-1 protein expression in damaged tubules paralleled mRNA expression. Kim-1 expression correlated with renal osteopontin, {alpha}-smooth muscle actin, and collagen III expression and with tubulointerstitial fibrosis. Damaged tubular segments expressing activated p38 also expressed Kim-1. Urinary Kim-1 was increased in Ren2 vs. SD (458 ± 70 vs. 27 ± 2 pg/ml, P < 0.01) rats and abolished in Ren2 rats treated with ramipril (33 ± 5 pg/ml, P < 0.01). Kim-1 is associated with development of RAS-mediated renal damage. Antifibrotic treatment through RAS blockade or p38 MAP kinase inhibition reduced Kim-1 in the homozygous Ren2 model.

homozygous TGR(mRen2)27; angiotensin II type 1 receptor


Address for reprint requests and other correspondence: M. H. de Borst, Dept. of Pathology and Laboratory Medicine, Univ. Medical Center Groningen and Univ. of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands (e-mail: m.h.de.borst{at}path.umcg.nl)




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