Reversal of glomerulosclerosis after high-dose enalapril treatment in subtotally nephrectomized rats
Reversal of glomerulosclerosis after high-dose enalapril treatment in subtotally nephrectomized rats
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DOI：
10.1097/01.asn.0000095248.91994.d3
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发表时间：
2003-11-01
影响因子：
13.6
通讯作者：
Ritz, E
中科院分区：
文献类型：
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作者：
Adamczak, M;Gross, ML;Ritz, E
干预阻断肾素-血管紧张素系统(RAS)可阻止肾损伤模型中肾损伤的进展。最近也有报道，已建立的肾小球硬化可以通过药物阻断RAS而逆转。这项研究的目的是证实大剂量的血管紧张素转换酶(ACE)抑制剂逆转已建立的肾小球硬化，并通过提供关于肾小球几何形状、足细胞和其他肾小球细胞、肾血管和肾小管间质组织的定量信息来扩大这一发现。雄性SD大鼠行肾次全切除(SNX)(n=27)或假手术(n=31)，按配对喂养方案饲养。术后8周，处死大鼠或分成两组：依那普利治疗组(48 mg/kg体重/d，连续4wk)或不治疗组。分别在8wk和12wk后，通过压力控制灌流固定的组织体视学方法评价肾脏的形态。SNX组大鼠的收缩压和白蛋白排泄率均显著高于假手术对照组。延迟依那普利治疗后SNX显著降低。肾小球硬化(GSI)、肾小管间质(TII)和血管(VI)损伤指数：SNX各剂量组均显著高于假手术对照组。在实验结束时(SNX后12wk)，延迟依那普利治疗的SNX的GSI、TII和VI(分别为0.77+/-0.18、0.63+/-0.19和0.43+/-0.16)显著低于未治疗的SNX(分别为1.64+/-0.14、1.16+/-0.34和0.67+/-0.29)。延迟依那普利治疗的SNX在8wk后GSI、TII和VI也显著低于未治疗的SNX。肾小球体积也是如此。SNX对足细胞数无影响，但足细胞体积增加。这两个指数仍未受到治疗的影响。依那普利延迟治疗后，SNX组肾小球系膜内细胞数和每肾小球内皮细胞数明显低于未治疗组。这些结果有力地提示了先前存在的损害，即肾小球、肾小管和血管重构的消退，以及ACE抑制剂治疗逆转肾小球肥大。研究证实，大剂量ACE抑制剂治疗可导致肾大部切除大鼠肾小球和间质病变的部分逆转。
Interventions to block the renin-angiotensin system (RAS) halt the progression of renal lesions in renal damage models. It has recently also been reported that established glomerulosclerosis can be reversed by pharmacologic blockade of the RAS. It was the aim of this study to confirm that high doses of angiotensin-converting enzyme (ACE) inhibitors reverse established glomerulosclerosis and to extend the findings by providing quantitative information on glomerular geometry, podocytes and other glomerular cells, renal vessels and tubulointerstitial tissue. Male Sprague Dawley rats were subjected to subtotal surgical renal ablation (SNX) (n = 27) or sham operation (n = 3 1) and fed using a pair-feeding protocol. Eight weeks after surgery, rats were either sacrificed or allocated to two arms: enalapril treatment (48 mg/kg body wt per day administered in the drinking fluid for 4 wk) or no treatment. Renal morphology was evaluated after 8 or 12 wk, respectively, by stereology in tissue fixed by pressure-controlled perfusion. Both systolic BP and albumin excretion rate were significantly higher in SNX compared with sham-operated controls. They were significantly reduced in SNX after delayed enalapril treatment. The glomerulosclerosis (GSI), tubulointerstitial (TII), and vascular (VI) damage indices were significantly higher in all SNX groups than in sham-operated controls. At the end of the experiment (12 wk after SNX) GSI, TII, and VI were significantly lower in SNX with delayed enalapril treatment (0.77 +/- 0.18, 0.63 +/- 0.19 and 0.43 +/- 0.16, respectively) compared with untreated SNX (1.64 +/- 0.14, 1.16 +/- 0.34 and 0.67 +/- 0.29, respectively). GSI, TII, and VI were also significantly lower in SNX with delayed enalapril treatment compared with SNX sacrificed without treatment 8 wk after SNX. The same was true for glomerular volume. The number of podocytes was not affected by SNX, but podocyte volume was increased. Both indices remained unaffected by treatment. The numbers of cells within the mesangium and endothelial cells per glomerulus were significantly lower in SNX after delayed enalapril treatment compared with untreated SNX. These results strongly suggest regression of preexisting lesions, i.e., glomerular, tubular, and vascular remodeling as well as reversal of glomerular hypertrophy by ACE inhibitor treatment. The study confirms that high-dose ACE inhibitor treatment causes partial reversal of glomerular as well as interstitial lesions in subtotally nephrectomized rats.