Angiotensin-converting enzyme (ACE) inhibitors are commonly used antiproteinuric drugs. Here we assessed the effect of the ACE inhibitor enalapril on the glomerular sieving coefficient of albumin (GSCA) using intravital multiphoton microscopy. Munich Wistar Frömter (MWF) rats were used as a model of hypertension-related glomerular lesions. Young (9-week-old) MWF rats were nonproteinuric, similar to what was observed in control Wistar rats. However, urinary albumin excretion in the MWF rats gradually increased during aging, averaging 0.00062 ± 0.0001 at age 9 weeks and 0.0054 ± 0.0003 (mg/mOsmol per liter) at age 52 weeks (P < 0.0001). Albuminuria in aged MWF rats was accompanied by structural changes, which were indicative of glomerular lesions. The GSCA was low in young MWF rats but increased markedly during aging, averaging 0.00057 ± 4.7 × 10(-5) (n = 25) in young MWF rats and 0.0027 ± 0.00036 in 52-week-old MWF rats (n = 36; P < 0.0001). Treatment of proteinuric 12-month-old MWF rats with enalapril over a 4-week period reduced the GSCA from 0.0027 ± 0.00036 to 0.00139 ± 0.00013 (P = 0.0005). Similarly, urinary albumin excretion was reduced, averaging 0.0051 ± 0.0003 and 0.0036 ± 0.0005 mg/mOsmol per liter before and after enalapril administration, respectively (P = 0.0089). In parallel, enalapril treatment reduced the mean arterial blood pressure (144.6 ± 6.5 mm Hg in untreated versus 110.9 ± 0.6 mm Hg in enalapril-treated MWF rats) and increased the glomerular filtration rate from 1.64 ± 0.3 ml/min to 3.58 ± 0.3 ml/min (P = 0.0025 versus baseline). In summary, enalapril reduced the GSCA in proteinuric MWF rats, which was paralleled by a similar reduction in urinary albumin excretion. These data suggest that glomerular rather than tubular mechanisms account for the beneficial antiproteinuric effects of the ACE inhibitor.
Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.