title: Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction.
abstract: Dipeptidyl peptidase IV (DPPIV) is an exopeptidase that modulates the function of several substrates, among which insulin-releasing incretin hormones are the most well known. DPPIV also modulate substrates involved in inflammation, cell migration, and cell differentiation. Although DPPIV is highly expressed in proximal renal tubular cells, the role of DPPIV inhibition in renal disease is not fully understood. For this reason, we investigated the effects of LC15-0444, a DPPIV inhibitor, on renal function in a mouse model of renal fibrosis. Eight-week-old C57/BL6 mice were subjected to unilateral ureteral obstruction (UUO) and were treated with LC15-0444 (a DPPIV inhibitor) at a dose of 150 mg/kg per day in food or vehicle for 14 days. DPPIV activity was significantly increased in obstructed kidneys, and reduced after treatment with LC15-0444. Administration of LC15-0444 resulted in a significant decrease in albuminuria, urinary excretion of 8-isoprostane, and renal fibrosis. DPPIV inhibition also substantially decreased the synthesis of several proinflammatory and profibrotic molecules, as well as the infiltration of macrophages. UUO significantly increased, and LC15-0444 markedly suppressed, levels of phosphorylated Smad2/3, TGFβ1, toll-like receptor 4, high-mobility group box-1, NADPH oxidase 4, and NF-κB. These results suggest that activation of DPPIV in the kidney has a role in the progression of renal disease and that targeted therapy inhibiting DPPIV may prove to be a useful new approach in the management of progressive renal disease, independent of mechanisms mediated by glucagon-like peptide-1.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Korea University Ansan-Hospital, Korea University, Ansan, Korea.
authors.forename: Hye Sook
authors.initials: HS
authors.lastname: Min
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Korea University Ansan-Hospital, Korea University, 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, Korea University, 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, Korea University, 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, Korea University, 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, Korea University, Ansan, Korea.
authors.forename: Mi Jin
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Wonkwang University, Gunpo, Korea.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Lee
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, Korea University, Ansan, Korea.
authors.forename: Jin Joo
authors.initials: JJ
authors.lastname: Cha
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Korea University Ansan-Hospital, Korea University, Ansan, Korea.
authors.forename: Young Yoon
authors.initials: YY
authors.lastname: Chung
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Sungkyunkwan University, Seoul, Korea.
authors.forename: Young Youl
authors.initials: YY
authors.lastname: Hyun
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, Korea University Ansan-Hospital, Korea University, Ansan, Korea.
authors.forename: Dae Ryong
authors.identifier: 0000000300632844
authors.initials: DR
authors.lastname: Cha
mesh_terms: D000818:Animals; D016207:Cytokines / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood / Q000652:urine; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D005355:Fibrosis / Q000188:drug therapy*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D010881:Piperidones; D011507:Proteinuria; D011743:Pyrimidines; D018709:Statistics, Nonparametric; D014517:Ureteral Obstruction / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D016207:Cytokines; D054873:Dipeptidyl-Peptidase IV Inhibitors; C534891:LC15-0444; D010881:Piperidones; D011743:Pyrimidines; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost