Renoprotective effects of a dipeptidyl peptidase 4 inhibitor in a mouse model of progressive renal fibrosis

• Published in: Renal failure 2017-01, Vol.39 (1), p.340-349
• Main Authors: Uchida, Takahiro, Oda, Takashi, Matsubara, Hidehito, Watanabe, Atsushi, Takechi, Hanako, Oshima, Naoki, Sakurai, Yutaka, Kumagai, Hiroo
• Format: Article
• Language: English
• Subjects: Actin; Actins - metabolism; Animals; Antigens, CD - metabolism; Antigens, Differentiation, Myelomonocytic - metabolism; Blood Urea Nitrogen; Chronic kidney disease; Collagen; Creatinine - blood; dipeptidyl peptidase 4; Dipeptidyl-peptidase IV; Dipeptidyl-Peptidase IV Inhibitors - therapeutic use; Disease Models, Animal; Fibrosis; Fibrosis - drug therapy; Fibrosis - metabolism; Gene expression; Inflammation; Kidney - drug effects; Kidney - pathology; Kidney diseases; Laboratory Study; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Peptidase; Pharmacology; Piperidines - therapeutic use; Receptors, Cell Surface - metabolism; renal fibrosis; renal inflammation; Renal Insufficiency, Chronic - drug therapy; Rodents; Smooth muscle; Surgery; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; unilateral ureteral obstruction; Uracil - analogs & derivatives; Uracil - therapeutic use; Ureteral Obstruction - complications
• ISSN: 0886-022X; 1525-6049
• DOI: 10.1080/0886022X.2017.1279553

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.