Induction of kidney injury molecule-1 in homozygous Ren2 rats is attenuated by blockade of the renin-angiotensin system or p38 MAP kinase.
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.
de Borst
Martin H
MH
Dept. of Pathology and Laboratory Medicine, Univ. Medical Center Groningen and Univ. of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands. m.h.de.borst@path.umcg.nl
van Timmeren
Mirjan M
MM
Vaidya
Vishal S
VS
de Boer
Rudolf A
RA
van Dalen
Mario B A
MB
Kramer
Andrea B
AB
Schuurs
Theo A
TA
Bonventre
Joseph V
JV
Navis
Gerjan
G
van Goor
Harry
H
D000450:Aldosterone / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D009320:Atrial Natriuretic Factor / Q000187:drug effects / Q000502:physiology; D001562:Benzimidazoles / Q000494:pharmacology; D015415:Biomarkers; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D003404:Creatinine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005355:Fibrosis; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D009395:Nephritis, Interstitial / Q000378:metabolism / Q000473:pathology; D053495:Osteopontin / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D012083:Renin / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013777:Tetrazoles / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D000450:Aldosterone; D047228:Angiotensin II Type 1 Receptor Blockers; D009320:Atrial Natriuretic Factor; D001562:Benzimidazoles; D015415:Biomarkers; D001713:Biphenyl Compounds; D015815:Cell Adhesion Molecules; D003404:Creatinine; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D053495:Osteopontin; D012083:Renin; D013777:Tetrazoles; D048051:p38 Mitogen-Activated Protein Kinases; C110936:Havcr1 protein, rat; C081643:candesartan