Functional and partial morphological regression of established renal injury in the obese zucker rat by blockade of the renin-angiotensin system.
OBJECTIVE
In experimental nephropathies, inhibitors of the renin-angiotensin-system (RAS) halted the progression, or even induced a regression in renal injury. We studied the potential of the angiotensin-converting enzyme (ACE) inhibitor perindopril and the angiotensin receptor blocker candesartan to reverse the established renal injury in the obese Zucker rat (OZR).


METHODS
Forty 4-week-old OZRs were uninephrectomized and fed a high-protein diet. After 16 weeks, they were randomized into 4 groups (n = 10 each) with comparable proteinuria: (1) control group sacrificed immediately for baseline data, and groups gavaged daily for 8 weeks with (2) placebo, (3) perindopril (1 mg/kg/day), or (4) candesartan (10 mg/kg/day).


RESULTS
Both drugs reduced systolic blood pressure (perindopril -16%, p < 0.001; candesartan -10%, p < 0.05), renal hypertrophy, and proteinuria (perindopril to 32%; candesartan to 37% of pretreatment values). Glomerulosclerosis was halted (perindopril p < 0.001; candesartan p < 0.05), and the numbers of glomerular endothelial and podocyte cells were restored. Mesangiolysis was reversed by perindopril. Metabolic and oxidative parameters were either stabilized (perindopril), or improved (candesartan).


CONCLUSIONS
In the OZR late inhibition of RAS halts the progression of glomerulosclerosis, reverses mesangiolysis and prevents the decline in glomerular endothelial cell and podocyte numbers. Tubulointerstitial fibrosis and vascular injury remain unchanged. Proteinuria shows marked regression.
Sebeková
Katarína
K
Department of Clinical and Experimental Pharmacotherapy, Slovak Medical University, Bratislava, Slovakia. katarina.sebekova@szu.sk
Lill
Maria
M
Boor
Peter
P
Heidland
August
A
Amann
Kerstin
K