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
Dept. of Pathology and Laboratory Medicine, Univ. Medical Center Groningen and Univ. of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.
Am J Physiol Renal Physiol. 2007 Jan;292(1):F313-20. doi: 10.1152/ajprenal.00180.2006. Epub 2006 Aug 8.
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.
肾损伤分子-1（Kim-1）与缺血性和蛋白尿性肾小管损伤相关；然而，肾素-血管紧张素系统（RAS）失调是否也能诱导Kim-1表达尚不清楚。我们研究了纯合Ren2大鼠中Kim-1的表达，该大鼠以RAS过度激活导致肾损伤为特征。我们还研究了抗纤维化治疗（RAS阻断或p38丝裂原活化蛋白激酶抑制）是否会影响Kim-1表达。7周龄时，纯合Ren2大鼠接受非降压剂量的坎地沙坦（0.05 mg·kg⁻¹·d⁻¹皮下注射）或p38抑制剂SB-239063（15 mg·kg⁻¹·d⁻¹皮下注射），持续4周；未治疗的Ren2和Sprague-Dawley（SD）大鼠作为对照。分别通过定量PCR和免疫组织化学测定Kim-1 mRNA和蛋白表达，并与肾纤维化前损伤标志物相关联。在8周龄的Ren2和SD大鼠中，测量有无血管紧张素转换酶抑制（雷米普利，饮用水中1 mg·kg⁻¹·d⁻¹，持续4周）情况下的尿Kim-1。未治疗的Ren2大鼠肾Kim-1 mRNA增加了20倍以上（以Kim-1与甘油醛-3-磷酸脱氢酶的比值表示）：SD大鼠为3.1±1.0，Ren2大鼠为75.5±43.6（P<0.01）。坎地沙坦和SB-239063显著降低Kim-1 mRNA：分别为3.1±1.5（P<0.01）和9.8±4.2（P<0.05）。受损肾小管中的Kim-1蛋白表达与mRNA表达平行。Kim-1表达与肾骨桥蛋白、α-平滑肌肌动蛋白和胶原蛋白III表达以及肾小管间质纤维化相关。表达活化p38的受损肾小管节段也表达Kim-1。Ren2大鼠的尿Kim-1高于SD大鼠（分别为458±70和27±2 pg/ml，P<0.01），而用雷米普利治疗的Ren2大鼠尿Kim-1消失（33±5 pg/ml，P<0.01）。Kim-1与RAS介导的肾损伤发展相关。通过RAS阻断或p38丝裂原活化蛋白激酶抑制进行的抗纤维化治疗可降低纯合Ren2模型中的Kim-1。
