Renoprotective effect of a dopamine D3 receptor antagonist in experimental type II diabetes
Renoprotective effect of a dopamine D3 receptor antagonist in experimental type II diabetes
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DOI：
10.1038/labinvest.3700383
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发表时间：
2006-03-01
影响因子：
5
通讯作者：
Ritz, E
中科院分区：
文献类型：
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作者：
Gross, MLP;Koch, A;Ritz, E
糖尿病肾病是导致终末期肾病的主要原因。多巴胺受体参与肾脏血流动力学的调节，并可能在糖尿病诱导的高滤过中发挥作用。为了验证这一假设，我们研究了多巴胺D3受体拮抗剂（D3-RA）在高血压II型糖尿病SHR/N-cp大鼠肾脏的影响。将瘦型和肥胖型SHR/N-cp大鼠随机分配至D3-RA、血管紧张素转换酶抑制剂（ACE-i）或D3-RA + ACE-i治疗组或对照组。给治疗的动物施用D3-RA A-437203（10 mg/kg/体重（BW）/天）或ACE-i群多普利（0.3 mg/kg BW/天）或两者的组合。灌注后6个月，通过形态学和体视学方法分析固定的肾脏。测定肾损伤指数（肾小球硬化、肾小球硬化损伤指数（GSI）、肾小管间质和血管损伤）、肾小球几何结构和功能变量，如尿白蛋白排泄、肾小球滤过率、血压、血液化学和BW。与非糖尿病对照组（0.4 +/-0.2）和治疗组（D3-RA：0.31 +/-0.12; ACE-i：0.2970.1;联合治疗：0.12 +/-0.01）相比，未治疗的糖尿病动物（1.62 +/-0.3）中的GSI（评分0-4）显著更高（P < 0.05）。与非糖尿病对照组（31 +/- 12）和治疗组（D3-RA：44 +/- 15; ACE-i：41 +/- 13;联合治疗：15 +/- 8）相比，未治疗糖尿病对照组（102 +/- 19）的尿白蛋白排泄量（mg/24 h）更高。与非糖尿病对照组和给药组相比，未治疗糖尿病动物的平均肾小球体积较高。结蛋白表达，足细胞损伤的标志物，在未治疗的糖尿病对照组中升高，在所有治疗组中降低。这些数据表明，在II型糖尿病模型中，多巴胺D3-RA对肾形态和白蛋白尿具有有益作用，其程度与ACE-i治疗相当。
Diabetic nephropathy is the leading cause of end-stage renal disease. Dopamine receptors are involved in the regulation of renal hemodynamics and may play a role in diabetes-induced hyperfiltration. To test this hypothesis, we investigated the renal effect of a dopamine D3 receptor antagonist (D3-RA) in hypertensive type II diabetic SHR/N-cp rats. Lean and obese SHR/N-cp rats were randomly assigned to D3-RA, angiotensin-converting enzyme inhibitor (ACE-i), or D3-RA + ACE-i treatment or control conditions. Treated animals were given the D3-RA A-437203 (10 mg/kg/ body weight (BW)/day) or the ACE-i trandolapril (0.3 mg/kg BW/day) or a combination of both. At 6 months following perfusion, fixed kidneys were analyzed by morphological and stereological methods. Indices of renal damage (glomerulosclerosis, glomerulosclerosis damage index (GSI), tubulointerstitial and vascular damage), glomerular geometry and functional variables such as urinary albumin excretion, glomerular filtration rate, blood pressure, blood chemistry and BW were determined. The GSI (score 0-4) was significantly higher (P < 0.05) in untreated diabetic animals (1.62 +/- 0.3) compared to nondiabetic controls (0.4 +/- 0.2) and the treatment groups (D3-RA: 0.31 +/- 0.12; ACE-i: 0.2970.1; combination treatment: 0.12 +/- 0.01). Urinary albumin excretion (mg/24 h) was higher in untreated diabetic controls (102 +/- 19) compared to nondiabetic controls (31 +/- 12) and the treatment groups (D3-RA: 44 +/- 15; ACE-i: 41 +/- 13; combination treatment: 15 +/- 8). Mean glomerular volume was higher in untreated diabetic animals compared to nondiabetic controls and to the treatment groups. Desmin expression, a marker of podocyte damage, was elevated in untreated diabetic controls and diminished in all treatment groups. These data suggest that in a model of type II diabetes, the dopamine D3-RA had a beneficial effect on renal morphology and albuminuria, which was comparable in magnitude to that of ACE-i treatment.