Podocyte repopulation contributes to regression of glomerular injury induced by ACE inhibition.
Angiotensin-converting enzyme (ACE) inhibition induces glomerular repair in the Munich Wistar Frömter (MWF) rat, a model of spontaneous glomerular injury. In this study, we investigated whether this effect is related to changes in glomerular cell number, particularly of podocytes, which are progressively lost with age. MWF rats with advanced nephropathy were studied at both 40 weeks and after 20 weeks of observation either with or without treatment with the ACE inhibitor lisinopril. Forty-week-old Wistar rats were used as controls. In untreated MWF rats, proteinuria, hypertension, glomerulosclerosis, and renal function worsened, while lisinopril induced regression of both functional and structural changes. Despite glomerular hypercellularity in untreated MWF rats, the number of endothelial cells per glomerulus did not change, and podocyte number even decreased. ACE inhibition halted the progressive increase in glomerular cell number and enhanced endothelial cell volume density. Surprisingly, lisinopril not only halted age-related podocyte loss but also increased the number of glomerular podocytes above baseline, which was associated with an increased number of proliferating Wilms tumor 1-positive cells, loss of cyclin-dependent kinase inhibitor p27 expression, and increased number of parietal podocytes. These data indicate that ACE inhibition restructures glomerular capillary, primarily by restoring the podocyte population in this model of glomerular injury. Increased parietal podocyte number in lisinopril-treated MWF rats suggests that the remodeling of Bowman's capsule epithelial cells contributes to this effect.
Macconi
Daniela
D
Mario Negri Institute for Pharmacological Research, Department of Biomedical Engineering, Laboratory of Renal Biophysics, Via Gavazzeni, 11, 24125 Bergamo, Italy. macconi@marionegri.it
Sangalli
Fabio
F
Bonomelli
Maria
M
Conti
Sara
S
Condorelli
Lucia
L
Gagliardini
Elena
E
Remuzzi
Giuseppe
G
Remuzzi
Andrea
A
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000633:toxicity*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002455:Cell Division; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy / Q000517:prevention & control; D006973:Hypertension / Q000188:drug therapy / Q000517:prevention & control; D007677:Kidney Function Tests; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology*; D017706:Lisinopril / Q000627:therapeutic use*; D008297:Male; D050199:Podocytes / Q000166:cytology*; D011507:Proteinuria / Q000188:drug therapy / Q000517:prevention & control; D051381:Rats; D011920:Rats, Inbred WF; D017208:Rats, Wistar
D000806:Angiotensin-Converting Enzyme Inhibitors; D017706:Lisinopril