title: Combination therapy with renin-angiotensin-aldosterone system inhibitor telmisartan and serine protease inhibitor camostat mesilate provides further renoprotection in a rat chronic kidney disease model.
abstract: We previously reported that camostat mesilate (CM) had renoprotective and antihypertensive effects in rat CKD models. In this study, we examined if CM has a distinct renoprotective effect from telmisartan (TE), a renin-angiotensin-aldosterone system (RAS) inhibitor, on the progression of CKD. We evaluated the effect of CM (400 mg/kg/day) and/or TE (10 mg/kg/day) on renal function, oxidative stress, renal fibrosis, and RAS components in the adenine-induced rat CKD model following 5-weeks treatment period. The combination therapy with CM and TE significantly decreased the adenine-induced increase in serum creatinine levels compared with each monotherapy, although all treatment groups showed similar reduction in blood pressure. Similarly, adenine-induced elevation in oxidative stress markers and renal fibrosis markers were significantly reduced by the combination therapy relative to each monotherapy. Furthermore, the effect of the combination therapy on plasma renin activity (PRA) and plasma aldosterone concentration (PAC) was similar to that of TE monotherapy, and CM had no effect on both PRA and PAC, suggesting that CM has a distinct pharmacological property from RAS inhibition. Our findings indicate that CM could be a candidate drug for an add-on therapy for CKD patients who had been treated with RAS inhibitors.
authors.affiliation: Center for Clinical Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Narita
authors.affiliation: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Ueda
authors.affiliation: Department of Internal Medicine III, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi, 409-3898, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Uchimura
authors.affiliation: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kakizoe
authors.affiliation: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Miyasato
authors.affiliation: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Mizumoto
authors.affiliation: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Morinaga
authors.affiliation: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Hayata
authors.affiliation: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Terumasa
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Adachi
authors.affiliation: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Miyoshi
authors.affiliation: Research Headquarters, Ono Pharmaceutical Co., Ltd., 1-8-2 Kyutaromachi, Chuo-ku, Osaka, 541-8564, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sakai
authors.affiliation: Center for Clinical Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kadowaki
authors.affiliation: Center for Clinical Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan.
authors.forename: Sumio
authors.initials: S
authors.lastname: Hirata
authors.affiliation: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Mukoyama
authors.affiliation: Department of Internal Medicine III, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi, 409-3898, Japan. Electronic address: kkenichiro@yamanashi.ac.jp.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Kitamura
mesh_terms: D000450:Aldosterone / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D001565:Benzoates / Q000008:administration & dosage* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004952:Esters; D005355:Fibrosis / Q000188:drug therapy; D016670:Gabexate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006146:Guanidines; D007668:Kidney / Q000473:pathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy*; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D000077333:Telmisartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D004952:Esters; D006146:Guanidines; D015842:Serine Proteinase Inhibitors; C034532:camostat; D000450:Aldosterone; D016670:Gabexate; D003404:Creatinine; D012083:Renin; D000077333:Telmisartan
keywords: Camostat mesilate; Chronic kidney diseases; Combination therapy; Serine protease inhibitor; Telmisartan