Effect of angiotensin-converting enzyme inhibition on glomerular basement membrane permeability and distribution of zonula occludens-1 in MWF rats.
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.
Macconi
Daniela
D
Department of Kidney Research, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Ghilardi
Marina
M
Department of Kidney Research, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Bonassi
Maria Enrica
ME
Department of Kidney Research, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Mohamed
Ehab I
EI
Department of Kidney Research, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Abbate
Mauro
M
Department of Kidney Research, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Colombi
Francesca
F
Department of Kidney Research, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Remuzzi
Giuseppe
G
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.
Remuzzi
Andrea
A
Department of Kidney Research, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism*; D019084:Fluorescent Antibody Technique, Indirect; D066298:In Vitro Techniques; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D017706:Lisinopril / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D016253:Microscopy, Immunoelectron; D010539:Permeability / Q000187:drug effects; D010750:Phosphoproteins / Q000378:metabolism*; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011922:Rats, Mutant Strains / Q000235:genetics; D014018:Tissue Distribution; D062826:Zonula Occludens-1 Protein
D000806:Angiotensin-Converting Enzyme Inhibitors; D008565:Membrane Proteins; D010750:Phosphoproteins; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; D017706:Lisinopril