Ma Guorong, Allen Terri J, Cooper Mark E, Cao Zemin
Danielle Alberti Memorial Centre for Diabetes Complications, Baker Medical Research Institute, Melbourne, Victoria, Australia.
Kidney Int. 2004 Sep;66(3):1090-8. doi: 10.1111/j.1523-1755.2004.00859.x.
Diabetic nephropathy is associated with increased albuminuria and accumulation of extracellular matrix proteins within the kidney. Clinical studies have shown some beneficial effects of calcium channel blockers (CCB) on diabetic nephropathy, even though they are generally considered to be less renoprotective than agents that interrupt the renin angiotensin system. However, effects of CCBs on renal injury, and in particular, expression of extracellular matrix proteins in a model of normotensive diabetic nephropathy, are poorly characterized.
Experimental diabetes was induced by injection of streptozocin in Sprague-Dawley rats. Amlodipine, a CCB which blocks the L channel, and mibefradil, a CCB blocking the T as well as the L channels, were given to diabetic rats for six months. Albumin excretion rate (AER), pathologic injury, and expression of the extracellular matrix proteins, collagen I, and fibronectin were assessed.
Increased AER in diabetic rats (13.2 x//1.3 mg/d, geometric mean x// tolerance factor) was attenuated by either amlodipine (3.2 x// 1.4 mg/d) or mibefradil (2.6 x// 1.4 mg/d). Increased glomerulosclerosis and tubulointerstitial injury in diabetic animals were attenuated by amlodipine and mibefradil. There was increased collagen accumulation in the kidney of diabetic rats as assessed by picro-sirius red staining. Gene expression of both collagen I and fibronectin were also increased in the kidneys from diabetic animals, as assessed by reverse transcription-polymerase chain reaction (RT-PCR). These markers of fibrosis were attenuated by treatment with either amlodipine or mibefradil. Blood pressure in diabetic rats (136 +/- 2 mm Hg) was modestly reduced by amlodipine (126 +/- 3 mm Hg) but not by mibefradil treatment (134 +/- 3 mm Hg).
Calcium channel blockers attenuated albuminuria, pathologic injury, and accumulation of extracellular matrix proteins in this normotensive model of diabetic nephropathy. These findings suggest that CCBs may be useful in preventing pathologic injury in the diabetic kidney.
糖尿病肾病与蛋白尿增加及肾脏细胞外基质蛋白积聚有关。临床研究显示钙通道阻滞剂（CCB）对糖尿病肾病有一些有益作用，尽管一般认为它们的肾脏保护作用不如阻断肾素血管紧张素系统的药物。然而，CCB对肾脏损伤的影响，特别是在正常血压糖尿病肾病模型中细胞外基质蛋白的表达，目前还不清楚。
通过向Sprague-Dawley大鼠注射链脲佐菌素诱导实验性糖尿病。将阻断L通道的CCB氨氯地平和同时阻断T及L通道的CCB米贝拉地尔给予糖尿病大鼠六个月。评估白蛋白排泄率（AER）、病理损伤以及细胞外基质蛋白、I型胶原和纤连蛋白的表达。
糖尿病大鼠升高的AER（几何平均数×耐受因子为13.2×//1.3mg/d）被氨氯地平（3.2×//1.4mg/d）或米贝拉地尔（2.6×//1.4mg/d）减弱。糖尿病动物中增加的肾小球硬化和肾小管间质损伤被氨氯地平和米贝拉地尔减轻。通过苦味酸天狼星红染色评估，糖尿病大鼠肾脏中的胶原积聚增加。通过逆转录聚合酶链反应（RT-PCR）评估，糖尿病动物肾脏中I型胶原和纤连蛋白的基因表达也增加。这些纤维化标志物通过氨氯地平或米贝拉地尔治疗而减弱。糖尿病大鼠的血压（136±2mmHg）被氨氯地平适度降低（126±3mmHg），但米贝拉地尔治疗后未降低（134±3mmHg）。
在这个正常血压的糖尿病肾病模型中，钙通道阻滞剂减弱了蛋白尿、病理损伤和细胞外基质蛋白的积聚。这些发现表明CCB可能对预防糖尿病肾脏的病理损伤有用。
