In proteinuric renal diseases, the
serine protease (SP)
plasmin activates the
epithelial sodium channel (ENaC) by cleaving its γ subunit. We previously demonstrated that a high-
salt (HS) diet provoked
hypertension and
proteinuria in Dahl
salt-sensitive (DS) rats, accompanied by γENaC activation, which were attenuated by
camostat mesilate (CM), an SP inhibitor. However, the effects of CM on
plasmin activity in DS rats remain unclear. In this study, we investigated the effects of CM on
plasmin activity, ENaC activation, and podocyte injury in DS rats. The DS rats were divided into the control diet, HS diet (8.0% NaCl), and HS+CM diet (0.1% CM) groups. After weekly blood pressure measurement and 24-h urine collection, the rats were sacrificed at 5 weeks. The HS group exhibited
hypertension, massive
proteinuria, increased urinary
plasmin, and γENaC activation; CM treatment suppressed these changes. CM prevented
plasmin(
ogen) attachment to podocytes and mitigated podocyte injury by reducing the number of apoptotic glomerular cells, inhibiting
protease-activated receptor-1 activation, and suppressing inflammatory and fibrotic
cytokine expression. Our findings highlight the detrimental role of urinary
plasmin in the pathogenesis of
salt-sensitive
hypertension and glomerular injury. Targeting
plasmin with SP inhibitors, such as CM, may be a promising therapeutic approach for these conditions.