Nakamura T, Obata J E, Onitsuka M, Shimada Y, Yoshida Y, Kawachi H, Shimizu F
Division of Blood Transfusion, Yamanashi Medical University, Yamanashi, Japan.
Nephron. 2000 Nov;86(3):315-26. doi: 10.1159/000045787.
Although the renoprotective effect of calcium-channel blockers (CCBs) has been examined in several models of hypertensive nephropathy, it remains unclear. It also remains to be clarified whether CCBs prevent the progression to end-stage renal failure in chronic progressive glomerulonephritis (GN). A new rat model of progressive mesangioproliferative GN was used to study the effect of benidipine hydrochloride, a long-acting dihydropyridine CCB, on the clinical features and morphological lesions.
This animal model of progressive GN was induced by a single intravenous injection of anti-Thy-1 monoclonal antibody (MoAb 1-22-3) two weeks after unilateral nephrectomy. After 10 weeks of treatment with benidipine (1, 3, and 5 mg/kg body weight, p.o.) or hydralazine (5 mg/kg body weight, p.o.), systolic blood pressure (SBP), urinary protein excretion, creatinine clearance, glomerulosclerosis index, tubulointerstitial lesion index, glomerular cross-sectional area, and glomerular expression of transforming growth factor-beta (TGF-beta) and alpha-smooth muscle actin (alpha-SMA) were measured.
Untreated rats developed hypertension, massive proteinuria, renal dysfunction, severe glomerular and tubulointerstitial injury, higher glomerular size, and marked glomerular staining for TGF-beta and alpha-SMA, while uninephrectomized control rats did not. Each dose of benidipine and hydralazine equally reduced SBP to uninephrectomized control levels. Three and five mg/kg/day of benidipine increased creatinine clearance, ameliorated glomerular and tubulointerstitial injury, and reduced glomerular staining for TGF-beta and alpha-SMA, but 1 mg/kg/day of benidipine and hydralazine failed. Only a dose of 5 mg/kg/day of benidipine reduced glomerular size, although it did not reduce the size to control levels.
These results indicate that in a rat model of progressive mesangioproliferative GN, benidipine prevents the progression to end-stage renal failure in a dose-dependent manner. This renoprotective action is associated with the suppression of glomerular expression of TGF-beta and alpha-SMA.
尽管钙通道阻滞剂（CCB）在多种高血压肾病模型中的肾脏保护作用已得到研究，但仍不明确。CCB是否能预防慢性进行性肾小球肾炎（GN）进展至终末期肾衰竭也有待阐明。本研究使用一种新的进行性系膜增生性GN大鼠模型，来研究长效二氢吡啶CCB盐酸贝尼地平对临床特征和形态学损伤的影响。
在单侧肾切除术后两周，通过单次静脉注射抗Thy-1单克隆抗体（MoAb 1-22-3）诱导建立这种进行性GN动物模型。在用贝尼地平（1、3和5mg/kg体重，口服）或肼屈嗪（5mg/kg体重，口服）治疗10周后，测量收缩压（SBP）、尿蛋白排泄、肌酐清除率、肾小球硬化指数、肾小管间质损伤指数、肾小球横截面积以及转化生长因子-β（TGF-β）和α-平滑肌肌动蛋白（α-SMA）的肾小球表达。
未经治疗的大鼠出现高血压、大量蛋白尿、肾功能不全、严重的肾小球和肾小管间质损伤、肾小球体积增大以及TGF-β和α-SMA的肾小球染色明显，而单侧肾切除的对照大鼠则未出现这些情况。各剂量的贝尼地平和肼屈嗪均将SBP同等程度降低至单侧肾切除对照水平。贝尼地平3mg/kg/天和5mg/kg/天可增加肌酐清除率，改善肾小球和肾小管间质损伤，并减少TGF-β和α-SMA的肾小球染色，但贝尼地平1mg/kg/天和肼屈嗪未能达到此效果。仅5mg/kg/天的贝尼地平剂量可减小肾小球体积，尽管未将其减小至对照水平。
这些结果表明，在进行性系膜增生性GN大鼠模型中，贝尼地平以剂量依赖方式预防进展至终末期肾衰竭。这种肾脏保护作用与抑制TGF-β和α-SMA的肾小球表达有关。
