选择性雌激素受体调节剂雷洛昔芬在糖尿病肾病动物模型中的肾脏保护作用。
Renoprotective effects of a selective estrogen receptor modulator, raloxifene, in an animal model of diabetic nephropathy.
作者信息
Dixon Alexis, Wells Corinne C, Singh Sandhya, Babayan Regina, Maric Christine
机构信息
Department of Medicine, Georgetown University Medical Center, Washington, DC 20057, USA.
出版信息
Am J Nephrol. 2007;27(2):120-8. doi: 10.1159/000099837. Epub 2007 Feb 15.
BACKGROUND/AIMS: Our previous studies have shown that supplementation with 17beta-estradiol (E2) from the onset of diabetes attenuates diabetic nephropathy. However, E2 is accompanied by feminizing effects as well as adverse side effects on other organs. The current study examined the renoprotective effects of a selective estrogen receptor modulator, raloxifene (RAL), in an experimental model of diabetic nephropathy. RAL activates estrogen receptors and estrogen-receptor-mediated cellular events without the side effects of E2.
METHODS
The study was performed in Sprague-Dawley nondiabetic (ND), streptozotocin-induced diabetic (D) and streptozotocin-induced D + RAL rats (n = 6/group).
RESULTS
After 12 weeks of treatment, D was associated with increased urine albumin excretion (ND: 4.2 +/- 0.4; D: 41.3 +/- 9.0 mg/day), glomerulosclerosis [glomerulosclerotic index; ND: 0.26 +/- 0.04; D: 1.86 +/- 0.80 arbitrary units (AU)], tubulointerstitial fibrosis (tubulointerstitial fibrosis index; ND: 0.37 +/- 0.05; D: 2.12 +/- 0.50 AU), increased collagen type I [ND: 1.31 +/- 0.07; D: 4.65 +/- 0.09 relative optical density (ROD)], collagen type IV (ND: 0.64 +/- 0.03; D: 1.37 +/- 0.11 ROD) and transforming growth factor beta (TGF-beta) protein expression (ND: 0.65 +/- 0.08; D: 1.25 +/- 0.10 ROD), increased density of CD68-positive cells (ND: 1.37 +/- 3.02; D: 29.2 +/- 1.74 cells/mm2) and increased plasma levels of interleukin-6 (ND: 14.8 +/- 5.0; D: 51.3 +/- 14.0 pg/ml). Treatment with RAL partially or fully attenuated these processes (urine albumin excretion: 21.0 +/- 5.0 mg/day; glomerulosclerotic index: 0.40 +/- 0.06 AU; tubulointerstitial fibrosis index: 0.20 +/- 0.04 AU; collagen type I: 2.55 +/- 0.49 ROD; collagen type IV: 0.70 +/- 0.09 ROD; TGF-beta: 0.91 +/- 0.08 ROD; CD68: 6.03 +/- 2.38 cells/mm2; interleukin-6: 31.2 +/- 5.0 pg/ml).
CONCLUSIONS
Our data indicate that treatment with RAL attenuates albuminuria and renal structural changes associated with diabetes.
背景/目的：我们之前的研究表明，从糖尿病发病开始补充17β-雌二醇（E2）可减轻糖尿病肾病。然而，E2会伴随女性化效应以及对其他器官的不良副作用。本研究在糖尿病肾病实验模型中检测了选择性雌激素受体调节剂雷洛昔芬（RAL）的肾脏保护作用。RAL可激活雌激素受体及雌激素受体介导的细胞事件，且无E2的副作用。
方法
本研究在斯普拉格-道利非糖尿病（ND）、链脲佐菌素诱导的糖尿病（D）以及链脲佐菌素诱导的D + RAL大鼠中进行（每组n = 6）。
结果
治疗12周后，糖尿病组出现尿白蛋白排泄增加（ND组：4.2±0.4；D组：41.3±9.0mg/天）、肾小球硬化[肾小球硬化指数；ND组：0.26±0.04；D组：1.86±0.80任意单位（AU）]、肾小管间质纤维化（肾小管间质纤维化指数；ND组：0.37±0.05；D组：2.12± .50 AU）、I型胶原增加[ND组：1.31±0.07；D组：4.65±0.09相对光密度（ROD）]、IV型胶原增加（ND组：0.64±0.03；D组：1.37±0.11 ROD）以及转化生长因子β（TGF-β）蛋白表达增加（ND组：0.65±0.08；D组：1.25±0.10 ROD）、CD68阳性细胞密度增加（ND组：1.37±3.02；D组：29.2±1.74个细胞/mm2）和血浆白细胞介素-6水平增加（ND组：14.8±5.0；D组：51. .3±14.0 pg/ml）。RAL治疗部分或完全减轻了这些过程（尿白蛋白排泄：21.0±5.0mg/天；肾小球硬化指数：0.40±0.06 AU；肾小管间质纤维化指数：0.20± .04 AU；I型胶原：2.55±0.49 ROD；IV型胶原：0.70±0.09 ROD；TGF-β：0.91±0.08 ROD；CD68：6.03±2.38个细胞/mm2；白细胞介素-6：31.2±5.0 pg/ml）。
结论
我们的数据表明，RAL治疗可减轻与糖尿病相关的蛋白尿和肾脏结构变化。
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