title: The serine protease inhibitor camostat mesilate attenuates the progression of chronic kidney disease through its antioxidant effects.
abstract: OBJECTIVE
  We have so far demonstrated the renoprotective effect of camostat mesilate (CM) in 5/6 nephrectomized rats at least partly through its antioxidant effect. However, precise mechanisms were not fully clarified. Therefore, we now examined the renoprotective and antioxidant mechanisms of CM by using the adenine-induced chronic kidney disease (CKD) rat model.
  
  
  METHODS
  In protocol 1, we analyzed the effect of CM on CKD. Rats were fed on a 0.75% adenine diet for 3 weeks to induce CKD followed by the experimental period with vehicle, CM, or hydralazine (HYD) treatment for 5 weeks. In protocol 2, we examined the safety of CM and HYD on the normal rats. In addition, we explored free radical scavenging activities of CM and its metabolites in vitro using electron paramagnetic resonance (EPR) spectroscopy.
  
  
  RESULTS
  CM, but not HYD, significantly reduced the serum creatinine levels, although both treatments showed similar reduction in the blood pressure. CM decreased mRNA expression and protein levels of fibrotic markers, the severity of renal fibrosis, the accumulation of oxidative stress, and the expression of NADPH oxidase components in the kidney. In the protocol 2, there were no statistically significant differences in general parameters except for the systolic blood pressure in HYD group. EPR study revealed that CM and its metabolites have potent hydroxyl radical scavenging activities in vitro.
  
  
  CONCLUSIONS
  Our findings indicate that CM significantly ameliorates the progression of CKD partly through its antioxidant effect independently from its blood pressure-lowering effect. Our results suggest the possibility that CM could be a new therapeutic agent that could arrest the progression of CKD.
authors.affiliation: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Ueda
authors.forename: Kohei
authors.initials: K
authors.lastname: Uchimura
authors.forename: Yuki
authors.initials: Y
authors.lastname: Narita
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Miyasato
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Mizumoto
authors.forename: Jun
authors.initials: J
authors.lastname: Morinaga
authors.forename: Manabu
authors.initials: M
authors.lastname: Hayata
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kakizoe
authors.forename: Masataka
authors.initials: M
authors.lastname: Adachi
authors.forename: Taku
authors.initials: T
authors.lastname: Miyoshi
authors.forename: Naoki
authors.initials: N
authors.lastname: Shiraishi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kadowaki
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sakai
authors.forename: Masashi
authors.initials: M
authors.lastname: Mukoyama
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Kitamura
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D000975:Antioxidants / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D018450:Disease Progression; D004952:Esters; D005355:Fibrosis; D016166:Free Radical Scavengers / Q000494:pharmacology; D016670:Gabexate / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006146:Guanidines; D006830:Hydralazine / Q000627:therapeutic use; D007668:Kidney / Q000473:pathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000473:pathology; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*
chemical_list: D000959:Antihypertensive Agents; D000975:Antioxidants; D004952:Esters; D016166:Free Radical Scavengers; D006146:Guanidines; D015842:Serine Proteinase Inhibitors; C034532:camostat; D006830:Hydralazine; D016670:Gabexate; D003404:Creatinine