TY - JOUR
T1 - Induction of kidney injury molecule-1 in homozygous Ren2 rats is attenuated by blockade of the renin-angiotensin system or p38 MAP kinase
AU - De Borst, Martin H.
AU - Van Timmeren, Mirjan M.
AU - Vaidya, Vishal S.
AU - De Boer, Rudolf A.
AU - Van Dalen, Mario B.A.
AU - Kramer, Andrea B.
AU - Schuurs, Theo A.
AU - Bonventre, Joseph V.
AU - Navis, Gerjan
AU - Van Goor, Harry
PY - 2007/1
Y1 - 2007/1
N2 - 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, α-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.
AB - 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, α-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.
UR - https://www.scopus.com/pages/publications/33846221517
U2 - 10.1152/ajprenal.00180.2006
DO - 10.1152/ajprenal.00180.2006
M3 - Article
C2 - 16896183
AN - SCOPUS:33846221517
SN - 1931-857X
VL - 292
SP - F313-F320
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 1
ER -