title: DA-1229, a dipeptidyl peptidase IV inhibitor, protects against renal injury by preventing podocyte damage in an animal model of progressive renal injury.
abstract: Although dipeptidyl peptidase IV (DPPIV) inhibitors are known to have renoprotective effects, the mechanism underlying these effects has remained elusive. Here we investigated the effects of DA-1229, a novel DPPIV inhibitor, in two animal models of renal injury including db/db mice and the adriamycin nephropathy rodent model of chronic renal disease characterized by podocyte injury. For both models, DA-1229 was administered at 300 mg/kg/day. DPPIV activity in the kidney was significantly higher in diabetic mice compared with their nondiabetic controls. Although DA-1229 did not affect glycemic control or insulin resistance, DA-1229 did improve lipid profiles, albuminuria and renal fibrosis. Moreover, DA-1229 treatment resulted in decreased urinary excretion of nephrin, decreased circulating and kidney DPPIV activity, and decreased macrophage infiltration in the kidney. In adriamycin-treated mice, DPPIV activity in the kidney and urinary nephrin loss were both increased, whereas glucagon-like peptide-1 concentrations were unchanged. Moreover, DA-1229 treatment significantly improved proteinuria, renal fibrosis and inflammation associated with decreased urinary nephrin loss, and kidney DPP4 activity. In cultured podocytes, DA-1229 restored the high glucose/angiotensin II-induced increase of DPPIV activity and preserved the nephrin levels in podocytes. These findings suggest that activation of DPPIV in the kidney has a role in the progression of renal disease, and that DA-1229 may exert its renoprotective effects by preventing podocyte injury.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Wonkwang University, Gunpo, Korea.
authors.forename: Jee
authors.initials: J
authors.lastname: Eun Lee
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Korea.
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Korea.
authors.forename: Mi Hwa
authors.initials: MH
authors.lastname: Lee
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Korea.
authors.forename: Hye Kyoung
authors.initials: HK
authors.lastname: Song
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Korea.
authors.forename: Jung Yeon
authors.initials: JY
authors.lastname: Ghee
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Korea.
authors.forename: Young Sun
authors.initials: YS
authors.lastname: Kang
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Korea.
authors.forename: Hye Sook
authors.initials: HS
authors.lastname: Min
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Wonkwang University, Gunpo, Korea.
authors.forename: Hyun Wook
authors.initials: HW
authors.lastname: Kim
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Korea.
authors.forename: Jin Joo
authors.initials: JJ
authors.lastname: Cha
authors.affiliation: Department of Pathology, Inha University, Incheon, Korea.
authors.forename: Jee Young
authors.initials: JY
authors.lastname: Han
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Inje University, Ilsan, Korea.
authors.forename: Sang Youb
authors.initials: SY
authors.lastname: Han
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Korea.
authors.forename: Dae Ryong
authors.initials: DR
authors.lastname: Cha
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D003928:Diabetic Nephropathies / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity; D018836:Inflammation Mediators / Q000097:blood / Q000652:urine; D007668:Kidney / Q000187:drug effects* / Q000293:injuries* / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000652:urine; D051379:Mice; D008810:Mice, Inbred C57BL; D053495:Osteopontin / Q000096:biosynthesis / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology*; D050199:Podocytes / Q000187:drug effects* / Q000473:pathology; D020011:Protective Agents / Q000494:pharmacology
chemical_list: C557982:4-(3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(tert-butoxymethyl)piperazin-2-one; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054873:Dipeptidyl-Peptidase IV Inhibitors; D018836:Inflammation Mediators; D008565:Membrane Proteins; D010879:Piperazines; D020011:Protective Agents; C506896:Spp1 protein, mouse; C113267:nephrin; D053495:Osteopontin; D004317:Doxorubicin; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse