title: Renoprotective effects of a dipeptidyl peptidase 4 inhibitor in a mouse model of progressive renal fibrosis.
abstract: Although the effects of dipeptidyl peptidase 4 (DPP-4) inhibitors beyond their hypoglycemic action have been reported, whether these inhibitors have renoprotective effects in nondiabetic chronic kidney disease (CKD) is unclear. We examined the therapeutic effects of DPP-4 inhibition in mice with unilateral ureteral obstruction (UUO), a nondiabetic model of progressive renal fibrosis. After UUO surgery, mice were administered either the DPP-4 inhibitor alogliptin or a vehicle by oral gavage once a day for 10 days. Physiological parameters, degrees of renal fibrosis and inflammation, and molecules related to renal fibrosis and inflammation were then evaluated using sham-operated mice as controls. Positive area of α-smooth muscle actin was significantly smaller and expression of transforming growth factor β messenger RNA was significantly lower in the alogliptin-treated group than in the vehicle-treated group. Renal total collagen content was also significantly lower in the alogliptin-treated group than in the vehicle-treated group. These results suggest that alogliptin exerted renoprotective antifibrotic effects. The positive area of F4/80 was significantly smaller and expression of CD68 messenger RNA was significantly lower in the alogliptin-treated group than in the vehicle-treated group, suggesting an anti-inflammatory action by the DPP-4 inhibitor. Compared to the results for the vehicle-treated group, expression of markers for M1 macrophages tended to be lower in the alogliptin-treated group, and the relative expression of M2 macrophages tended to be higher. These data indicate the various protective effects of DPP-4 inhibition in nondiabetic mice with UUO. DPP-4 inhibitors may therefore be promising therapeutic choices even for nondiabetic CKD patients.
authors.affiliation: a Department of Nephrology and Endocrinology , National Defense Medical College , Tokorozawa , Saitama , Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Uchida
authors.affiliation: b Department of Nephrology , Tokyo Medical University Hachioji Medical Center , Hachioji , Tokyo , Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Oda
authors.affiliation: a Department of Nephrology and Endocrinology , National Defense Medical College , Tokorozawa , Saitama , Japan.
authors.forename: Hidehito
authors.initials: H
authors.lastname: Matsubara
authors.affiliation: a Department of Nephrology and Endocrinology , National Defense Medical College , Tokorozawa , Saitama , Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: a Department of Nephrology and Endocrinology , National Defense Medical College , Tokorozawa , Saitama , Japan.
authors.forename: Hanako
authors.initials: H
authors.lastname: Takechi
authors.affiliation: a Department of Nephrology and Endocrinology , National Defense Medical College , Tokorozawa , Saitama , Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Oshima
authors.affiliation: c Department of Preventive Medicine and Public Health , National Defense Medical College , Tokorozawa , Saitama , Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sakurai
authors.affiliation: a Department of Nephrology and Endocrinology , National Defense Medical College , Tokorozawa , Saitama , Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Kumagai
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001806:Blood Urea Nitrogen; D002135:Calcium-Binding Proteins; D003404:Creatinine / Q000097:blood; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000188:drug therapy* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000627:therapeutic use*; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014498:Uracil / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014517:Ureteral Obstruction / Q000150:complications; D000097382:CD68 Molecule
chemical_list: D000199:Actins; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002135:Calcium-Binding Proteins; D003404:Creatinine; D054873:Dipeptidyl-Peptidase IV Inhibitors; D010880:Piperidines; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D016212:Transforming Growth Factor beta; D014498:Uracil; C000634132:Adgre1 protein, mouse; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C544013:alpha-smooth muscle actin, mouse; C520853:alogliptin
keywords: Chronic kidney disease; dipeptidyl peptidase 4; renal fibrosis; renal inflammation; unilateral ureteral obstruction