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Angiotensin-Converting
Enzyme Inhibition Prevents Loss of Glomerular Hydraulic Permeability in
Passive Heymann Nephritis |
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Andrea Remuzzi,
Nives Monaci, Maria Enrica Bonassi, Daniela Corna, Carla Zoja, Ehab I. Mohammed,
and Giuseppe Remuzzi |
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Department
of Kidney Research (AR, NM, MEB, DC, CZ, EIM, GR), Mario Negri Institute
for Pharmacological Research, Bergamo, Italy; and Unit of Nephrology and
Dialysis (GR), Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Bergamo,
Italy |
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SUMMARY: 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. |
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