title: Anti-inflammatory role of DPP-4 inhibitors in a nondiabetic model of glomerular injury.
abstract: Dipeptidyl peptidase (DPP)-4 is an enzyme that cleaves and inactivates incretin hormones capable of stimulating insulin secretion from pancreatic β-cells. DPP-4 inhibitors are now widely used for the treatment of type 2 diabetes. Experimental studies have suggested a renoprotective role of DPP-4 inhibitors in various models of diabetic kidney disease, which may be independent of lowering blood glucose levels. In the present study, we examined the effect of DPP-4 inhibitors in the rat Thy-1 glomerulonephritis model, a nondiabetic glomerular injury model. Rats were injected with OX-7 (1.2 mg/kg iv) and treated with the DPP-4 inhibitor alogliptin (20 mg·kg(-1)·day(-1)) or vehicle for 7 days orally by gavage. Alogliptin significantly reduced the number of CD68-positive inflammatory macrophages in the kidney, which was associated with a nonsignificant tendency to ameliorate glomerular injury and reduce proteinuria. Another DPP-4 inhibitor, anagliptin (300 mg·kg(-1)·day(-1) mixed with food) and a glucagon-like peptide-1 receptor agonist, exendin-4 (10 mg/kg sc), similarly reduced CD68-positive macrophage infiltration to the kidney. Furthermore, ex vivo transmigration assays using peritoneal macrophages revealed that exendin-4, but not alogliptin, dose dependently reduced monocyte chemotactic protein-1-stimulated macrophage infiltration. These data suggest that DPP-4 inhibitors reduced macrophage infiltration directly via glucagon-like peptide-1-dependent signaling in the rat Thy-1 nephritis model and indicate that the control of inflammation by DPP-4 inhibitors is useful for the treatment of nondiabetic kidney disease models.
authors: Division of Nephrology and Endocrinology, The University of Tokyo School of Medicine, Tokyo, Japan.
authors: Yoshiki
authors: Y
authors: Higashijima
authors: Division of Nephrology and Endocrinology, The University of Tokyo School of Medicine, Tokyo, Japan tetsu-tky@umin.ac.jp.
authors: Tetsuhiro
authors: T
authors: Tanaka
authors: Division of Nephrology and Endocrinology, The University of Tokyo School of Medicine, Tokyo, Japan.
authors: Junna
authors: J
authors: Yamaguchi
authors: Division of Nephrology and Endocrinology, The University of Tokyo School of Medicine, Tokyo, Japan.
authors: Shinji
authors: S
authors: Tanaka
authors: Division of Nephrology and Endocrinology, The University of Tokyo School of Medicine, Tokyo, Japan.
authors: Masaomi
authors: M
authors: Nangaku
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D000961:Antilymphocyte Serum; D002460:Cell Line; D018932:Chemokine CCL2 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D019610:Cytoprotection; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D000077270:Exenatide; D005921:Glomerulonephritis / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000067757:Glucagon-Like Peptide-1 Receptor; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D011507:Proteinuria / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control; D011743:Pyrimidines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D014688:Venoms / Q000494:pharmacology; D000097382:CD68 Molecule
chemical_list: D000893:Anti-Inflammatory Agents; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000961:Antilymphocyte Serum; D018932:Chemokine CCL2; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D010880:Piperidines; D011743:Pyrimidines; D018027:Receptors, Glucagon; D014498:Uracil; D014688:Venoms; C539355:CD68 protein, rat; D000097382:CD68 Molecule; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; C545245:Dpp4 protein, mouse; C520853:alogliptin; C583175:anagliptin
keywords: dipeptidyl peptidase-4; glucagon-like peptide-1; nondiabetic kidney disease