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1 Pathology and Laboratory Medicine, University Medical Center Groningen and University of Groningen, Groningen, groningen, Netherlands
2 Pathology and Laboratory Medicine, University Medical Center Groningen, Groningen, Netherlands
3 Medicine-Renal, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
4 Surgery, University Medical Center Groningen and University of Groningen, Groningen, groningen, Netherlands
5 Harvard Institutes of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States
6 Internal Medicine, University Medical Center Groningen and University of Groningen, Groningen, groningen, Netherlands
7 Pathology, Univ. Med. Center Groningen, Groningen, Netherlands
* To whom correspondence should be addressed. E-mail: m.h.de.borst{at}path.umcg.nl.
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. Furthermore, we investigated whether antifibrotic treatment (RAS blockade or p38 MAP kinase inhibition) would affect Kim-1 expression.
Seven-wk old homozygous Ren2 rats received a non-hypotensive dose of candesartan (0.05 mg/kg/day s.c.) or the p38 inhibitor SB239063 (15 mg/kg/day s.c.) for 4 wks; untreated Ren2 and Sprague Dawley (SD) rats served as controls. Kim-1 mRNA (qPCR) and protein (IHC) expression were determined and related to markers of prefibrotic renal damage. Urinary Kim-1 was measured in 8-wk old Ren2 and SD rats with and without ACE inhibition (ramipril 1 mg/kg/day in drinking water for 4 wks).
Untreated Ren2 rats showed >20-fold increased renal Kim-1 mRNA (ratio Kim-1/GAPDH 75.5±43.6 vs 3.1±1.0 in SD, p<0.01). Both candesartan (3.1±1.5, p<0.01) and SB239063 (9.8±4.2, p<0.05) strongly reduced Kim-1 mRNA. Kim-1 protein expression in damaged tubules paralleled mRNA expression. Kim-1 expression correlated with renal osteopontin, 
-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 (458±70 pg/ml) vs SD (27±2, p<0.01) and abolished in Ren2 animals treated with ramipril (33±5, p<0.01).
Kim-1 is associated with the development of RAS-mediated renal damage. Antifibrotic treatment through RAS blockade or p38 MAP kinase inhibition reduces Kim-1 in the homozygous Ren2 model.
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