Angiotensin receptor blockade decreases fibrosis and fibroblast expression in a rat model of unilateral ureteral obstruction.
OBJECTIVE
Unilateral ureteral obstruction is characterized by histopathological changes including interstitial fibrosis, fibroblast specific protein expression, tubular atrophy and apoptosis, and macrophage infiltration. Angiotensin II has been implicated in some of these changes. We examined the effect of angiotensin blockade on markers of renal injury, including fibroblast specific protein expression, fibrosis, apoptosis and macrophage infiltration. We used losartan, an angiotensin II antagonist, in a unilateral ureteral obstruction model and studied animals 3 weeks after unilateral ureteral obstruction, a time at which renal damage is well established.


METHODS
Rats underwent unilateral ureteral obstruction and were given either drinking water or losartan for 21 days. Kidneys were harvested and examined for fibrosis (trichrome and the Sircol assay for collagen), apoptosis (TUNEL), and fibroblast specific protein expression and macrophage infiltration (immunohistochemistry).


RESULTS
Unilateral ureteral obstruction was found to induce fibrosis, apoptosis, fibroblast expression and macrophage in the obstructed kidney. Losartan significantly decreased apoptosis and macrophage infiltration in the obstructed kidney. It also decreased fibrosis, as measured by either trichrome staining assessed by a pathologist, the Sircol assay for collagen or fibroblast specific protein expression. However, approximately 50% of the changes were not affected by the current treatment, suggesting that other factors contribute to renal damage in unilateral ureteral obstruction.


CONCLUSIONS
We observed the direct contribution of angiotensin II to both apoptotic and cellular transition processes (epithelial mesenchymal transition) and fibrosis in unilateral ureteral obstruction. Because these processes are active not only in unilateral ureteral obstruction, but also in other renal diseases, the value of angiotensin II blockade as an important part of the antifibrotic armamentarium has been confirmed.
Kellner
Daniel
D
Institute for Pediatric Urology, Weill Cornell Medical College, New York, New York 10021, USA.
Chen
Jie
J
Richardson
Ingride
I
Seshan
Surya V
SV
El Chaar
Maher
M
Vaughan
E D
ED
Poppas
Dix
D
Felsen
Diane
D
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects*; D005355:Fibrosis; D019808:Losartan / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014513:Ureter / Q000473:pathology*; D014517:Ureteral Obstruction / Q000473:pathology* / Q000517:prevention & control*
D047228:Angiotensin II Type 1 Receptor Blockers; D019808:Losartan