Effect of ramipril, nifedipine, and moxonidine on glomerular morphology and podocyte structure in experimental renal failure
Effect of ramipril, nifedipine, and moxonidine on glomerular morphology and podocyte structure in experimental renal failure
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DOI：
10.1093/oxfordjournals.ndt.a027447
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发表时间：
1996-06-01
影响因子：
6.1
通讯作者：
Ritz, E
中科院分区：
文献类型：
--
作者：
Amann, K;Nichols, C;Ritz, E
背景。实验性肾衰竭引起肾脏的结构改变。目前尚不清楚抗高血压治疗如何改变这些变化。研究目的：研究不同降压药（雷米普利、硝苯地平、莫硝定）对肾小球几何形状、细胞数量、细胞形态和毛细血管化的影响。材料和方法。研究了假手术雄性SD大鼠和部分全肾切除（SNX）自由喂养大鼠。每组8-10只SNX大鼠分别给予雷米普利（0.5 mg/kg体重/天）、硝苯地平（30 mg/kg体重/天）或莫索尼定（10 mg/kg体重/天）治疗。灌注固定后用体视技术观察肾脏。收缩压（通过尾部容积描记）sham-op组为110+/-13 mmHg， SNX组为119+/-9 mmHg。雷米普利（89+11 mmHg）、硝苯地平（98+23 mmHg）和莫昔定（92+11 mmHg）均可有效地将血压降至正常值以下。SNX组与sham-op组相比，肾小球硬化指数（GSI）显著升高；雷米普利和莫硝定也有类似的效果，但硝苯地平效果较差。所有治疗均可减轻血管损伤（肾小球前血管），而只有雷米普利和莫昔定可显著减轻小管间质损伤。SNX组平均肾小球簇体积比假手术组增加。对照组，仅经雷米普利治疗恢复正常。三种降压药对肾小球细胞的影响不同。在肾大部切除后，足细胞体积和每肾小球系膜细胞数量增加。硝苯地平和雷米普利在较小程度上阻止系膜细胞增生。相反，只有ACE抑制剂雷米普利，而硝苯地平或莫硝定不能预防足细胞异常，特别是足细胞肥大。(i)尽管收缩压降低程度相当，但不同类别的降压药对肾半全切除大鼠肾损害的影响不同。这一观察结果与抗高血压药物的特异性非血流动力学作用一致。（ii）肾小球和小管间质损伤可通过ACE抑制剂和抗交感疾病药物治疗预防，但不能通过钙拮抗剂硝苯地平治疗。相反，硝苯地平也能预防肾血管改变。（iii）只有ACE抑制剂能有效抑制足细胞肥大和系膜细胞增生。ACE抑制剂对肾小球硬化的优越作用是否与抑制肾小球生长和足细胞肥大以及保存足细胞结构有关，或者这些发现是否仅仅是更大疗效的被动反映，目前还没有定论。
Background. Experimental renal failure causes structural alterations of the kidney. It is still unresolved how these changes are modified by antihypertensive treatment.Purpose of the study. To examine the effects of different antihypertensive agents (ramipril, nifedipine, moxonidine) mainly on glomerular geometry, cell number, cell morphology, and capillarization, in a subtotal nephrectomy model of renal failure.Material and methods. Sham-operated male SD rats and subtotally nephrectomized (SNX) ad libitum-fed rats were examined. Groups of 8-10 SNX rats were left untreated or were treated with ramipril (0.5 mg/kg b.w. per day), nifedipine (30 mg/kg b.w. per day) or moxonidine(10 mg/kg b.w. per day) respectively. After perfusion fixation the kidneys were examined using stereological techniques.Results. Systolic blood pressure (by tail plethysmography) was 110+/-13 mmHg in sham-op and 119+/-9 in SNX. It was effectively and comparably reduced below normal values by ramipril (89+11 mmHg), nifedipine (98+23 mmHg) and moxonidine (92+11 mmHg). The glomerulosclerosis index (GSI) was significantly increased in SNX versus sham-op; it was similarly decreased by ramipril and moxonidine but less so by nifedipine. Vascular damage (preglomerular vessels) was reduced by all treatments whereas tubulointerstitial damage was significantly reduced only by ramipril and moxonidine. Mean glomerular tuft volume was increased in SNX compared to sham-op. controls and was normalized only by ramipril treatment. Glomerular cells were differentially affected by the three antihypertensive agents. After subtotal nephrectomy an increase in podocyte volume and mesangial cell number per glomerulus was noted. Nifedipine, and to a lesser extent ramipril, prevented mesangial cell hyperplasia. In contrast, only the ACE inhibitor ramipril, but not nifedipine or moxonidine prevented podocyte abnormalities, particularly podocyte hypertrophy.Conclusions. (i) Despite comparable reduction in systolic blood pressure, different classes: of antihypertensive agents had diverse effects on renal damage in subtotally nephrectomized rat. This observation is consistent with specific, non-hemodynamic actions of anti-hypertensives. (ii) Glomerular and tubulointerstitial damage are prevented by treatment with ACE inhibitors and antisympathotonic agents, but not with the calcium antagonist nifedipine. In contrast, renal vascular changes were also prevented by nifedipine. (iii) Only ACE inhibitors effectively inhibited podocyte hypertrophy and mesangial cell hyperplasia. Whether the superior effect of ACE inhibitors on glomerulosclerosis is related to inhibiton of glomerular growth and podocyte hypertrophy as well as preservation of podocyte structure, or whether these findings are merely a passive reflection of greater efficacy, remains unresolved.