In
nephrotic syndrome, aberrant glomerular filtration of
plasminogen and conversion to active
plasmin in preurine are thought to activate proteolytically
epithelial sodium channel (ENaC) and contribute to
sodium retention and
edema. The ENaC blocker
amiloride is an off-target inhibitor of
urokinase-type plasminogen activator (uPA) in vitro. It was hypothesized that uPA is abnormally filtered to preurine and is inhibited in urine by
amiloride in
nephrotic syndrome. This was tested by determination of Na(+) balance, uPA
protein and activity, and
amiloride concentration in urine from rats with
puromycin aminonucleoside (PAN)-induced
nephrotic syndrome. Urine samples from 6 adult and 18 pediatric patients with
nephrotic syndrome were analyzed for uPA activity and
protein. PAN treatment induced significant
proteinuria in rats which coincided with increased urine uPA
protein and activity, increased urine
protease activity, and total
plasminogen/
plasmin concentration and Na(+) retention.
Amiloride (2 mg·kg(-1)·24 h(-1)) concentration in urine was in the range 10-20 μmol/l and reduced significantly urine uPA activity,
plasminogen activation,
protease activity, and
sodium retention in PAN rats, while
proteinuria was not altered. In paired urine samples, uPA
protein was significantly elevated in urine from children with active
nephrotic syndrome compared with remission phase. In six adult nephrotic patients, urine uPA
protein and activity correlated positively with 24 h urine
protein excretion. In conclusion,
nephrotic syndrome is associated with aberrant filtration of uPA across the injured glomerular barrier.
Amiloride inhibits urine uPA activity which attenuates
plasminogen activation and urine
protease activity in vivo. Urine uPA is a relevant target for
amiloride in vivo.