URINARY PLASMIN PLAYS PATHOGENIC ROLES FOR THE DEVELOPMENT OF HYPERTENSION IN SALT-SENSITIVE HYPERTENSION WITH PROTEINURIA

Abstract

Objective: The epithelial sodium channel (ENaC) in the renal collecting duct plays pivotal roles in the regulation of sodium homeostasis and blood pressure. The proteolytic cleavage of γENaC by extracellular serine proteases is an important process for the full activation of this channel and is physiologically regulated by aldosterone. In the setting of proteinuria, plasminogen/plasmin filtered through damaged glomeruli could activate ENaC leading to hypertension, independently of aldosterone. We reported that Dahl salt-sensitive (DS) rats with high-salt (HS) diet developed severe hypertension together with aberrant activation of γENaC by serine proteases. However, the role of plasmin in the hypertension of DS rats remain to be elucidated. In this study, we evaluated the relationship of proteinuria, urinary plasmin activity and hypertension, and the antihypertensive effect of a serine protease inhibitor camostat mesilate (CM) in DS rats. Design and method: Five-week-old DS rats were divided into normal-salt (NS) diet, HS and HS+CM (0.1% diet) groups. After systolic BP (SBP) measurement and 24h urine collection were performed for 5 weeks, rats were sacrificed for biochemical examination. Urinary plasmin activities were evaluated by zymography and Western blotting (WB). The proteolytic cleavage of γENaC in urinary exosome was evaluated by WB. Results: HS diet induced severe hypertension, marked proteinuria and urinary plasmin activation, as well as the cleavage of urinary exosomal γENaC. The treatment with CM suppressed these changes, together with significantly reduced BP and proteinuria [SBP (mmHg): NS, 141.1 ± 5.8; HS, 222.3 ± 15.4; HS + CM, 199.5 ± 5.0. urinary protein (mg/day): NS, 23.8 ± 12.1; HS 272.3 ± 79.9; HS ± CM, 135.1 ± 27.4]. Conclusions: In conclusion, plasmin is associated with the pathogenesis of hypertension in DS rats, and serine protease inhibition could be a potential therapeutic strategy against salt-sensitive hypertension with proteinuria.