Li Can, Yang Chul Woo, Park Cheol Whee, Ahn Hee Jong, Kim Wan Young, Yoon Kun Ho, Suh Sun Hee, Lim Sun Woo, Cha Jung Ho, Kim Yong Soo, Kim Jin, Chang Yoon Sik, Bang Byung Kee
Department of Internal Medicine and Anatomy, The Catholic University of Korea, Seoul, Korea.
Kidney Int. 2003 Feb;63(2):454-63. doi: 10.1046/j.1523-1755.2003.00751.x.
Osteopontin (OPN) mediates progressive renal injury in various renal diseases by attracting macrophages, and its expression is regulated by the renin-angiotensin system (RAS). We studied the association between OPN expression and tubulointerstitial injury, and investigated the effect of ramipril on OPN expression in an animal model of non-insulin-dependent diabetes mellitus (NIDDM): Otsuka Long-Evans Tokushima Fatty (OLETF) rats.
Control (Long-Evans Tokushima Otsuka, LETO) and diabetic (OLETF) rats were treated with ramipril (3 mg/kg in drinking water) or vehicle for nine months, starting at 20 weeks of age. Systolic blood pressure, body weight, urinary protein excretion and oral glucose tolerance tests (OGTT) were monitored periodically. Renal function, histology (glomerulosclerosis, tubulointerstitial fibrosis, and ED-1-positive cells as a measure of macrophage infiltration), and expressions of OPN and transforming growth factor-beta1 (TGF-beta1) were evaluated at the end of the study.
Compared with the LETO rats, OLETF rats showed declines in creatinine clearance rate, increases in urinary protein excretion and systolic blood pressure, and development of glomerulosclerosis, tubulointerstitial fibrosis, and inflammatory cell infiltration (all P < 0.05). Blocking angiotensin II with ramipril significantly improved all of these parameters (all P < 0.01). At the molecular level, expressions of OPN and TGF-beta1 were up-regulated in the OLETF rats, and were markedly suppressed following ramipril treatment. The sites of strong OPN mRNA and protein expressions were localized to areas of renal injury. Of note, the expression of OPN mRNA was strongly correlated with the number of ED-1-positive cells (r = 0.560, P = 0.01) and the tubulointerstitial fibrosis score (r = 0.500, P < 0.05).
Up-regulation of OPN expression may play a role in tubulointerstitial injury associated with diabetic nephropathy, and blockade of the RAS by ramipril may confer renoprotection by decreasing OPN expression in non-insulin-dependent diabetic nephropathy.
骨桥蛋白（OPN）通过吸引巨噬细胞介导各种肾脏疾病中的进行性肾损伤，其表达受肾素-血管紧张素系统（RAS）调节。我们研究了OPN表达与肾小管间质损伤之间的关联，并在非胰岛素依赖型糖尿病（NIDDM）动物模型：大冢长-艾氏-德岛肥胖（OLETF）大鼠中研究了雷米普利对OPN表达的影响。
对照组（大冢长-艾氏-德岛大鼠，LETO）和糖尿病组（OLETF）大鼠从20周龄开始，用雷米普利（饮用水中3mg/kg）或赋形剂处理9个月。定期监测收缩压、体重、尿蛋白排泄和口服葡萄糖耐量试验（OGTT）。在研究结束时评估肾功能、组织学（肾小球硬化、肾小管间质纤维化以及作为巨噬细胞浸润指标的ED-1阳性细胞）以及OPN和转化生长因子-β1（TGF-β1）的表达。
与LETO大鼠相比，OLETF大鼠肌酐清除率下降、尿蛋白排泄和收缩压升高，出现肾小球硬化、肾小管间质纤维化和炎性细胞浸润（所有P<0.05）。用雷米普利阻断血管紧张素II可显著改善所有这些参数（所有P<0.01）。在分子水平上，OPN和TGF-β1的表达在OLETF大鼠中上调，而在雷米普利治疗后明显受到抑制。OPN mRNA和蛋白强表达部位定位于肾损伤区域。值得注意的是，OPN mRNA的表达与ED-1阳性细胞数量（r=0.560，P=0.01）和肾小管间质纤维化评分（r=0.500，P<0.05）密切相关。
OPN表达上调可能在糖尿病肾病相关的肾小管间质损伤中起作用，雷米普利阻断RAS可能通过降低非胰岛素依赖型糖尿病肾病中OPN的表达而发挥肾脏保护作用。
