Salt-sensitive
hypertension is associated with poor clinical outcomes. The
epithelial sodium channel (ENaC) in the kidney plays pivotal roles in
sodium reabsorption and blood pressure regulation, in which its γ subunit is activated by extracellular
serine proteases. In proteinuric nephropathies,
plasmin filtered through injured glomeruli reportedly activates γENaC in the distal nephron and causes podocyte injury. We previously reported that Dahl
salt-sensitive (DS) rats fed a high-
salt (HS) diet developed
hypertension and
proteinuria along with γENaC activation and that a synthetic
serine protease inhibitor,
camostat mesilate, mitigated these changes. However, the role of
plasmin in DS rats remained unclear. In this study, we evaluated the relationship between
plasmin and
hypertension as well as podocyte injury and the effects of
plasmin inhibitors in DS rats. Five-week-old DS rats were divided into normal-
salt diet, HS diet, and HS+plasmin inhibitor (either
tranexamic acid [TA] or synthetic
plasmin inhibitor YO-2) groups. After blood pressure measurement and 24 h urine collection over 5 weeks, rats were sacrificed for biochemical analyses. The HS group displayed severe
hypertension and
proteinuria together with activation of
plasmin in urine and γENaC in the kidney, which was significantly attenuated by YO-2 but not TA. YO-2 inhibited the attachment of
plasmin(
ogen) to podocytes and alleviated podocyte injury by inhibiting apoptosis and inflammatory/profibrotic
cytokines. YO-2 also suppressed upregulation of
protease-activated receptor-1 and phosphorylated ERK1/2. These results indicate an important role of
plasmin in the development of
salt-sensitive
hypertension and related podocyte injury, suggesting
plasmin inhibition as a potential therapeutic strategy.