title: Angiotensin-converting enzyme inhibition prevents loss of glomerular hydraulic permeability in passive heymann nephritis.
abstract: 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.
authors.affiliation: Department of Kidney Research, Mario Negri Institute for Pharmacological Research, Bergamo, Italy. aremuzzi@cyberg.it
authors.forename: A
authors.initials: A
authors.lastname: Remuzzi
authors.forename: N
authors.initials: N
authors.lastname: Monaci
authors.forename: M E
authors.initials: ME
authors.lastname: Bonassi
authors.forename: D
authors.initials: D
authors.lastname: Corna
authors.forename: C
authors.initials: C
authors.lastname: Zoja
authors.forename: E I
authors.initials: EI
authors.lastname: Mohammed
authors.forename: G
authors.initials: G
authors.lastname: Remuzzi
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001485:Basement Membrane / Q000648:ultrastructure; D002463:Cell Membrane Permeability; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000201:enzymology* / Q000503:physiopathology / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D007703:Peptidyl-Dipeptidase A