title: Novel Therapeutic Role for Dipeptidyl Peptidase III in the Treatment of Hypertension.
abstract: Dipeptidyl peptidase III (DPP III) cleaves dipeptide residues from the N terminus of polypeptides ranging from 3 to 10 amino acids in length and is implicated in pathophysiological processes through the breakdown of certain oligopeptides or their fragments. In this study, we newly identified the biochemical properties of DPP III for angiotensin II (Ang II), which consists of 8 amino acids. DPP III quickly and effectively digested Ang II with Km = 3.7×10(-6) mol/L. In the in vivo experiments, DPP III remarkably reduced blood pressure in Ang II-infused hypertensive mice without alteration of heart rate. DPP III did not affect hemodynamics in noradrenalin-induced hypertensive mice or normotensive mice, suggesting specificity for Ang II. When DPP III was intravenously injected every other day for 4 weeks after Ang II osmotic minipump implantation in mice, Ang II-induced cardiac fibrosis and hypertrophy were significantly attenuated. This DPP III effect was at least similar to that caused by an angiotensin receptor blocker candesartan. Furthermore, administration of DPP III dramatically reduced the increase in urine albumin excretion and kidney injury and inflammation markers caused by Ang II infusion. Both DPP III and candesartan administration showed slight additive inhibition in the albumin excretion. These results reveal a novel potential use of DPP III in the treatment of hypertension and its protective effects on hypertension-sensitive organs, such as the heart and kidneys.
authors.affiliation: From the Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology (X.P., A.S., S.Kurita, D.P.Z., K.T., H.O.), Division of Diabetology, Endocrinology, Nephrology, and Neurology, Department of Medicine, Shiga University of Medical Science, Otsu, Japan (M.Y-Y., S.Kume); Chemistry Division, Department of Chemistry, Biology and Marine Science, Faculty of Science, University of the Ryukyus, Nishihara-cho, Japan (T.I.); and Department of Emergency, The Fourth Affiliated Hospital of China Medical University, Shenyang, China (X.P.).
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Pang
authors.affiliation: From the Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology (X.P., A.S., S.Kurita, D.P.Z., K.T., H.O.), Division of Diabetology, Endocrinology, Nephrology, and Neurology, Department of Medicine, Shiga University of Medical Science, Otsu, Japan (M.Y-Y., S.Kume); Chemistry Division, Department of Chemistry, Biology and Marine Science, Faculty of Science, University of the Ryukyus, Nishihara-cho, Japan (T.I.); and Department of Emergency, The Fourth Affiliated Hospital of China Medical University, Shenyang, China (X.P.).
authors.forename: Akio
authors.initials: A
authors.lastname: Shimizu
authors.affiliation: From the Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology (X.P., A.S., S.Kurita, D.P.Z., K.T., H.O.), Division of Diabetology, Endocrinology, Nephrology, and Neurology, Department of Medicine, Shiga University of Medical Science, Otsu, Japan (M.Y-Y., S.Kume); Chemistry Division, Department of Chemistry, Biology and Marine Science, Faculty of Science, University of the Ryukyus, Nishihara-cho, Japan (T.I.); and Department of Emergency, The Fourth Affiliated Hospital of China Medical University, Shenyang, China (X.P.).
authors.forename: Souichi
authors.initials: S
authors.lastname: Kurita
authors.affiliation: From the Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology (X.P., A.S., S.Kurita, D.P.Z., K.T., H.O.), Division of Diabetology, Endocrinology, Nephrology, and Neurology, Department of Medicine, Shiga University of Medical Science, Otsu, Japan (M.Y-Y., S.Kume); Chemistry Division, Department of Chemistry, Biology and Marine Science, Faculty of Science, University of the Ryukyus, Nishihara-cho, Japan (T.I.); and Department of Emergency, The Fourth Affiliated Hospital of China Medical University, Shenyang, China (X.P.).
authors.forename: Dimitar P
authors.initials: DP
authors.lastname: Zankov
authors.affiliation: From the Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology (X.P., A.S., S.Kurita, D.P.Z., K.T., H.O.), Division of Diabetology, Endocrinology, Nephrology, and Neurology, Department of Medicine, Shiga University of Medical Science, Otsu, Japan (M.Y-Y., S.Kume); Chemistry Division, Department of Chemistry, Biology and Marine Science, Faculty of Science, University of the Ryukyus, Nishihara-cho, Japan (T.I.); and Department of Emergency, The Fourth Affiliated Hospital of China Medical University, Shenyang, China (X.P.).
authors.forename: Keisuke
authors.initials: K
authors.lastname: Takeuchi
authors.affiliation: From the Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology (X.P., A.S., S.Kurita, D.P.Z., K.T., H.O.), Division of Diabetology, Endocrinology, Nephrology, and Neurology, Department of Medicine, Shiga University of Medical Science, Otsu, Japan (M.Y-Y., S.Kume); Chemistry Division, Department of Chemistry, Biology and Marine Science, Faculty of Science, University of the Ryukyus, Nishihara-cho, Japan (T.I.); and Department of Emergency, The Fourth Affiliated Hospital of China Medical University, Shenyang, China (X.P.).
authors.forename: Mako
authors.initials: M
authors.lastname: Yasuda-Yamahara
authors.affiliation: From the Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology (X.P., A.S., S.Kurita, D.P.Z., K.T., H.O.), Division of Diabetology, Endocrinology, Nephrology, and Neurology, Department of Medicine, Shiga University of Medical Science, Otsu, Japan (M.Y-Y., S.Kume); Chemistry Division, Department of Chemistry, Biology and Marine Science, Faculty of Science, University of the Ryukyus, Nishihara-cho, Japan (T.I.); and Department of Emergency, The Fourth Affiliated Hospital of China Medical University, Shenyang, China (X.P.).
authors.forename: Shinji
authors.initials: S
authors.lastname: Kume
authors.affiliation: From the Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology (X.P., A.S., S.Kurita, D.P.Z., K.T., H.O.), Division of Diabetology, Endocrinology, Nephrology, and Neurology, Department of Medicine, Shiga University of Medical Science, Otsu, Japan (M.Y-Y., S.Kume); Chemistry Division, Department of Chemistry, Biology and Marine Science, Faculty of Science, University of the Ryukyus, Nishihara-cho, Japan (T.I.); and Department of Emergency, The Fourth Affiliated Hospital of China Medical University, Shenyang, China (X.P.).
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ishida
authors.affiliation: From the Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology (X.P., A.S., S.Kurita, D.P.Z., K.T., H.O.), Division of Diabetology, Endocrinology, Nephrology, and Neurology, Department of Medicine, Shiga University of Medical Science, Otsu, Japan (M.Y-Y., S.Kume); Chemistry Division, Department of Chemistry, Biology and Marine Science, Faculty of Science, University of the Ryukyus, Nishihara-cho, Japan (T.I.); and Department of Emergency, The Fourth Affiliated Hospital of China Medical University, Shenyang, China (X.P.). hogita@belle.shiga-med.ac.jp.
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Ogita
mesh_terms: D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000378:metabolism / Q000494:pharmacology*; D004195:Disease Models, Animal; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D008813:Mice, Inbred ICR; D011897:Random Allocation; D012380:Role; D012680:Sensitivity and Specificity; D016896:Treatment Outcome
chemical_list: D000804:Angiotensin II; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C100152:dipeptidyl peptidase III
keywords: acute kidney injury; angiotensin II; blood pressure; cardiomegaly; dipeptidyl peptidase III; kinetics