Urinary prostasin in humans: relationships among prostasin, aldosterone and epithelial sodium channel activity

Abstract

Prostasin, a membrane-bound serine protease, is known to increase the activity of the epithelial sodium channel (ENaC). Gene expression of prostasin was shown to be regulated by aldosterone, which increases the rate of sodium reabsorption through ENaC. To clarify the physiological relationships among prostasin, aldosterone and ENaC, we developed a specific radioimmunoassay (RIA) for human prostasin. Prostasin levels in urine were determined in 26 normotensive and 121 hypertensive subjects. Aldosterone content in urine and plasma, urinary Na/K ratio and other clinical parameters were also measured. We observed a highly significant correlation between prostasin and aldosterone concentration in urine (correlation coefficient: 0.673, Po0.0001). A significant correlation was also found between urinary prostasin and plasma aldosterone concentration (correlation coefficient: 0.229, Po0.05). In addition, urinary prostasin excretion was inversely correlated with urinary Na/K ratio (correlation coefficient: À0.425, Po0.0001). In conclusion, we developed a prostasin-specific RIA and applied it to the clinical study. Our findings suggest that urinary prostasin level is strongly correlated with urinary or plasma aldosterone level and may serve as a surrogate marker for ENaC activation in hypertensive patients. However, it is not clear, at the present time, whether endogenous aldosterone regulates prostasin expression or vice versa.

Prostasin interacts with the epithelial Na+channel and facilitates cleavage of the γ-subunit by a second protease

“…Prostasin is released into renal tubules, and its urinary concentration increases in response to aldosterone infusion in rats (29). A correlation between aldosterone levels and urinary prostasin excretion has been reported in humans (27). To gain further insights regarding the mechanism(s) by which prostasin activates ENaC, we conducted biochemical and functional experiments with wild-type prostasin and a catalytically inactive mutant (S238A).…”

Physiological regulation of epithelial sodium channel by proteolysis

“…Although several studies support a role for prostasin in the kidney in vivo [41][42][43][44], a causal link between prostasin and ENaC activation has not been demonstrated.…”

“…Apart from inhibition of enzymatic activity, the endogenous GPIspecific phospholipase D1 (Gpld1) appears to be involved in regulated cell surface shedding of prostasin [50]. The physiological consequences of endogenous GPI-specific phospholipases in vivo are not known, but appear to be relevant since prostasin is present in urine under normal conditions [43].…”

Prostasin and matriptase (ST14) in placenta from preeclamptic and healthy pregnant women

“…Prostasin could affect blood pressure by cleaving the ectodomain of the ENaC y-subunit in kidney [18,28]. This causes channel activation and promotes reabsorption of sodium and water [29]. We observed increased level of prostasin in urine from preeclampsia patients, which correlated with urine protein.…”