ACE inhibition reduces glomerulosclerosis and regenerates glomerular tissue in a model of progressive renal disease.
Today angiotensin II inhibition is primarily used to slow the rate of progression of kidney diseases. There is evidence that these therapies can induce a partial regression of glomerular lesions. However, we do not know yet the extent of sclerotic lesion regression and whether new glomerular tissue is formed to help support the renal function. We used male Munich Wistar Fromter (MWF) rats, an experimental model for progressive kidney disease, to quantify kidney structural lesions upon angiotensin-converting enzyme (ACE) inhibition therapy. Animals were studied at 50 weeks of age, when renal function and structure are severely altered, and after a 10-week observation period, without or with treatment with lisinopril (80 mg/l in drinking water). A group of untreated Wistar rats was used as controls. With age, proteinuria, and serum creatinine worsen, but lisinopril almost normalized proteinuria and stabilized serum creatinine. Serial section analysis of whole glomerular tufts showed that at baseline, glomerulosclerosis affected the entire glomerular population, and that these changes further increased with age. Lisinopril significantly reduced incidence and extent of glomerulosclerosis, with the presence of glomerular tufts not affected by sclerosis (23% of glomeruli). Glomerular volume was not significantly affected by treatment, and glomerular mass spared from sclerosis increased from 46.9 to 65.5% upon treatment, indicating consistent regeneration of glomerular tissue. Lisinopril normalized baseline glomerular transforming growth factor-beta and alpha-smooth muscle actin overexpression, and prevented worsening of interstitial changes. Hence, ACE inhibition, which is widely used in human kidney disease, may not only halt the progression of renal failure, but also actually induce the regeneration of new renal tissue.
Remuzzi
A
A
Department of Biomedical Engineering, Mario Negri Institute for Pharmacological Research, Bergamo, Italy. aremuzzi@marionegri.it
Gagliardini
E
E
Sangalli
F
F
Bonomelli
M
M
Piccinelli
M
M
Benigni
A
A
Remuzzi
G
G
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002196:Capillaries / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000473:pathology; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D017706:Lisinopril / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012038:Regeneration; D012079:Renal Circulation; D016212:Transforming Growth Factor beta / Q000032:analysis
D000806:Angiotensin-Converting Enzyme Inhibitors; D016212:Transforming Growth Factor beta; D017706:Lisinopril