Abstract: SA-PO1086
The Effect of Serine Protease Inhibition on Glomerular Injuries in Salt-Sensitive Hypertension
Session Information
- Hypertension: Basic and Experimental - Treatment and Mechanisms
November 04, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Hypertension
- 1102 Hypertension: Basic and Experimental - Renal Causes and Consequences
Authors
- Iwata, Yasunobu, Department of Nephrology, Kumamoto university graduate school of medical sciences, Kumamoto, Japan
- Kakizoe, Yutaka, Department of Nephrology, Kumamoto university graduate school of medical sciences, Kumamoto, Japan
- Nakagawa, Terumasa, Department of Nephrology, Kumamoto university graduate school of medical sciences, Kumamoto, Japan
- Izumi, Yuichiro, Department of Nephrology, Kumamoto university graduate school of medical sciences, Kumamoto, Japan
- Kuwabara, Takashige, Department of Nephrology, Kumamoto university graduate school of medical sciences, Kumamoto, Japan
- Adachi, Masataka, Department of Nephrology, Kumamoto university graduate school of medical sciences, Kumamoto, Japan
- Kitamura, Kenichiro, University of Yamanashi Faculty of Medicine, Chuou, Yamanashi, Japan
- Mukoyama, Masashi, Department of Nephrology, Kumamoto university graduate school of medical sciences, Kumamoto, Japan
Background
We previously reported that a synthetic serine protease (SP) inhibitor, camostat mesylate (CM), suppressed epithelial sodium channel (ENaC) activation by SPs and exerted an antihypertensive effect in Dahl salt-sensitive (DS) rats. Furthermore, CM significantly attenuated proteinuria even before it exerted BP lowering effect, suggesting that some SPs are involved in glomerular injuries independently of BP. Recently, it was reported that plasminogen filtered through damaged glomeruli was activated to plasmin by tPA expressed on the surface of podocytes, and that plasmin could directly cause podocyte injuries. We conducted this study to identify SPs which could be associated with glomerular injuries and to explore therapeutic effects of SP inhibition on glomerular injuries in salt-sensitive hypertension.
Methods
Four-week-old male DS rats were divided into following three groups: control group (0.3% NaCl), high-salt (HS) group (8% NaCl diet), and HS＋CM group (HS＋0.1%CM diet). After systolic BP measurement and 24h urine collection were performed, rats were sacrificed at day 7. SP activities were evaluated by zymography.
Results
HS group did not develop hypertension but displayed significant proteinuria at day 7, which was attenuated in HS+CM (Urinary TP (mg/day); control 4.09±1.17, HS 42.01±3.72, HS+CM 14.31±7.63). CM did not mitigate glomerular hyperfiltration reflected by increased creatinine clearance (Ccr) with salt loading (Ccr (mL/h); control 0.3±0.1, HS 0.8±0.1, HS+CM 0.8±0.2). Urinary plasmin activation was induced by HS, which was substantially inhibited by HS+CM. Furthermore, CM also suppressed albuminuria as early as at day 1-2 even when any apparent activation of SPs was not detected in urine.
Conclusion
Our current study indicates that plasmin and other unknown SPs would be involved in the pathogenesis of glomerular injuries, suggesting that SP inhibition could be a new strategy for the treatment of renal injuries in salt-sensitive hypertension.