In several models of renal
disease progression,
angiotensin-converting enzyme (
ACE) inhibitors reduced
proteinuria and limited glomerulosclerosis, which suggested that reduction of renal
angiotensin II (Ang II) activity is crucial for the preservation of glomerular structure and function. However, it cannot be ruled out that other hormonal systems, including inhibition of the
bradykinin breakdown, also play a role. We compared the effects of chronic treatment with the
ACE inhibitor lisinopril with those of a specific Ang II receptor antagonist,
L-158,809, on
proteinuria and renal injury in passive
Heymann nephritis (PHN), a model of immune renal disease that closely resembles human
membranous nephropathy, with long-lasting
proteinuria followed by tubulointerstitial damage and glomerulosclerosis. Passive
Heymann nephritis was induced with 0.5 mL/100 g of rabbit anti-Fx1A antibody in 24 male Sprague-Dawley rats. The animals were divided into three groups of eight rats each, and were given the following in the
drinking water on a daily basis:
lisinopril (40 mg/L),
L-158,809 (50 mg/L), or no
therapy. Treatment started at day 7 (
proteinuria was already present) and lasted 12 months. Eight normal rats were used as controls. Untreated PHN rats developed
hypertension, while rats with PHN given
lisinopril or
L-158,809 all had systolic blood pressure values even lower than those of normal rats. Urinary
protein excretion progressively increased with time in untreated PHN rats, who developed tubulointerstitial damage and glomerulosclerosis. Both
lisinopril and
L-158,809 exhibited a potent antiproteinuric effect and preserved glomerular and tubular structural integrity at a similar extent. Renal gene expression of
transforming growth factor-beta and
extracellular matrix proteins was also effectively reduced by the two treatments. These results indicate that
ACE inhibitors and Ang II receptor antagonists are equally effective in preventing renal injury in PHN and suggest that the renoprotective effects of
ACE inhibitors in this model are solely due to inhibition of Ang II.