Macconi Daniela, Ghilardi Marina, Bonassi Maria Enrica, Mohamed Ehab I, Abbate Mauro, Colombi Francesca, Remuzzi Giuseppe, Remuzzi Andrea
Department of Kidney Research, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Unit of Nephrology and Dialysis, Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Bergamo, Italy.
J Am Soc Nephrol. 2000 Mar;11(3):477-489. doi: 10.1681/ASN.V113477.
The mechanism(s) by which angiotensin-converting enzyme (ACE) inhibitors prevent glomerular membrane loss of permselective function is still not understood. In male MWF rats, which develop spontaneous proteinuria with age, ACE inhibitors prevent proteinuria and increase glomerular ultrafiltration coefficient. These renoprotective effects are not associated with ultrastructural changes of capillary wall components. This study was undertaken to investigate whether ACE inhibitors modulate functional properties of glomerular basement membrane (GBM) and/or of epithelial cells, both of which have been suggested to play a role in the maintenance of the glomerular filtration barrier. The hydraulic and macromolecular permeability of the GBM were determined, by an in vitro filtration system, in untreated or lisinopril-treated rats and in Wistar rats taken as controls. By indirect immunofluorescence and immunoelectron microscopy, glomerular distribution of the tight junction protein zonula occludens- (ZO-1), a component of the slit diaphragm, was also studied. Results document that spontaneous proteinuria in MWF rats develops without significant changes in the permeability of the GBM to water and albumin, or in the ultrastructure of the podocyte foot processes, but is associated with an important alteration in the distribution of ZO-1 at the glomerular level. Lisinopril, which prevented proteinuria, also prevented glomerular redistribution of the protein. Thus, renoprotective effects of ACE inhibitors are not associated with changes in intrinsic functional properties of GBM, or ultrastructural changes of the epithelial cells, but rather with preservation of glomerular ZO-1 distribution and slit diaphragm function, which are essential for maintaining the filtration barrier.
血管紧张素转换酶（ACE）抑制剂预防肾小球膜选择性通透功能丧失的机制仍不清楚。在雄性MWF大鼠中，随着年龄增长会自发出现蛋白尿，ACE抑制剂可预防蛋白尿并增加肾小球超滤系数。这些肾脏保护作用与毛细血管壁成分的超微结构变化无关。本研究旨在调查ACE抑制剂是否调节肾小球基底膜（GBM）和/或上皮细胞的功能特性，这两者均被认为在维持肾小球滤过屏障中起作用。通过体外过滤系统测定未治疗或赖诺普利治疗的大鼠以及作为对照的Wistar大鼠的GBM的水力和大分子通透性。通过间接免疫荧光和免疫电子显微镜，还研究了紧密连接蛋白闭合蛋白-1（ZO-1）（裂孔隔膜的一个组成部分）在肾小球的分布。结果表明，MWF大鼠的自发性蛋白尿在GBM对水和白蛋白的通透性或足细胞足突的超微结构方面没有显著变化的情况下发生，但与ZO-1在肾小球水平的分布发生重要改变有关。预防蛋白尿的赖诺普利也可预防该蛋白在肾小球的重新分布。因此，ACE抑制剂的肾脏保护作用与GBM内在功能特性的变化或上皮细胞的超微结构变化无关，而是与肾小球ZO-1分布和裂孔隔膜功能的保留有关，这对于维持滤过屏障至关重要。
