Induction of kidney injury molecule-1 in homozygous Ren2 rats is attenuated by blockade of the renin-angiotensin system or p38 MAP kinase

• Published in: American journal of physiology. Renal physiology 2007-01, Vol.292 (1), p.F313-F320
• Main Authors: de Borst, Martin H, van Timmeren, Mirjan M, Vaidya, Vishal S, de Boer, Rudolf A, van Dalen, Mario B A, Kramer, Andrea B, Schuurs, Theo A, Bonventre, Joseph V, Navis, Gerjan, van Goor, Harry
• Format: Article
• Language: English
• Subjects: Aldosterone - metabolism; Angiotensin II Type 1 Receptor Blockers - pharmacology; Animals; Animals, Genetically Modified; Atrial Natriuretic Factor - drug effects; Atrial Natriuretic Factor - physiology; Benzimidazoles - pharmacology; Biomarkers; Blood Pressure - physiology; Cell Adhesion Molecules - biosynthesis; Creatinine - metabolism; Enzyme Inhibitors - pharmacology; Enzyme-Linked Immunosorbent Assay; Fibrosis; Immunohistochemistry; Male; Membrane Proteins - biosynthesis; Nephritis, Interstitial - metabolism; Nephritis, Interstitial - pathology; Osteopontin - biosynthesis; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; Rats; Rats, Inbred Strains; Renin - genetics; Renin-Angiotensin System - drug effects; Reverse Transcriptase Polymerase Chain Reaction; Tetrazoles - pharmacology
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00180.2006

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 x kg(-1) x day(-1) sc) or the p38 inhibitor SB-239063 (15 mg x kg(-1) x 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 x kg(-1) x 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.