Remuzzi A, Monaci N, Bonassi M E, Corna D, Zoja C, Mohammed E I, Remuzzi G
Department of Kidney Research, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Lab Invest. 1999 Dec;79(12):1501-10.
We used morphometric techniques and theoretical analysis to investigate structural and functional changes of the glomerular membrane that develop in passive Heymann nephritis (PHN), an experimental model of human membranous glomerulopathy The effect of angiotensin-converting enzyme (ACE) inhibition on the above parameters was also investigated to explore the mechanisms by which this treatment exerts functional and structural protection at the renal tissue level. Morphometric analysis of glomerular capillary by light and electron microscopy was performed in normal control rats and in rats injected with rabbit anti-Fx 1A antibody, 12 months after induction of PHN. A group of PHN rats treated with lisinopril during the observation period was also investigated. Glomerular capillary architecture was not significantly altered in PHN rats, thus glomerular volume and capillary lumen volume were comparable with normal controls; only mesangial volume was significantly elevated in PHN rats. Glomerular membrane structure was significantly affected by PHN: the thickness of the glomerular basement membrane (GBM) increased, and the frequency of epithelial filtration slits decreased. Electron-dense deposits in the subepithelial space of the GBM were estimated to occupy more than 20% of the GBM area. Theoretical analysis of glomerular hydraulic permeability allowed us to predict that, after these structural changes, the permeability of the GBM and the epithelial layer significantly decreased, with an average reduction in the ultrafiltration coefficient (Kf) of approximately 43%. ACE inhibition limited mesangial expansion and prevented changes of glomerular epithelial cells (filtration slit frequency) but not GBM thickening. Immune deposits within the GBM were only partially prevented by lisinopril. A selective effect on epithelial permeability was calculated in lisinopril-treated rats, and a partial preservation of Kf reduction was observed. These results suggest that structural changes of the GBM and epithelial cells that develop in PHN are responsible for the reduced filtration capacity observed in this model. ACE inhibition only partially prevented immune-deposits in the GBM and favorably affected epithelial cell structure. These selective effects on glomerular podocytes may contribute to preserve water and macromolecule permeability of the glomerular capillary wall in this immunologic model of kidney disease.
我们运用形态计量学技术和理论分析方法，研究了被动型海曼肾炎（PHN）（一种人类膜性肾小球病的实验模型）中肾小球膜的结构和功能变化。同时也研究了血管紧张素转换酶（ACE）抑制对上述参数的影响，以探究该治疗方法在肾组织水平发挥功能和结构保护作用的机制。在诱导PHN 12个月后，对正常对照大鼠以及注射兔抗Fx 1A抗体的大鼠进行了光镜和电镜下肾小球毛细血管的形态计量分析。还对一组在观察期内接受赖诺普利治疗的PHN大鼠进行了研究。PHN大鼠的肾小球毛细血管结构未发生显著改变，因此肾小球体积和毛细血管腔体积与正常对照相当；仅PHN大鼠的系膜体积显著增加。PHN对肾小球膜结构有显著影响：肾小球基底膜（GBM）厚度增加，上皮滤过裂隙频率降低。GBM上皮下间隙中的电子致密沉积物估计占GBM面积的20%以上。肾小球水力通透性的理论分析使我们预测，在这些结构变化之后，GBM和上皮层的通透性显著降低，超滤系数（Kf）平均降低约43%。ACE抑制限制了系膜扩张，并防止了肾小球上皮细胞的变化（滤过裂隙频率），但未能阻止GBM增厚。赖诺普利仅部分阻止了GBM内的免疫沉积物。在接受赖诺普利治疗的大鼠中计算出了对上皮通透性的选择性作用，并观察到Kf降低得到了部分保留。这些结果表明，PHN中GBM和上皮细胞的结构变化是该模型中观察到的滤过能力降低的原因。ACE抑制仅部分阻止了GBM中的免疫沉积物，并对上皮细胞结构产生了有利影响。这些对肾小球足细胞的选择性作用可能有助于在这种肾脏疾病的免疫模型中维持肾小球毛细血管壁的水和大分子通透性。
