Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction

Hye Sook Min, Jung Eun Kim, Mi Hwa Lee, Hye Kyoung Song, Young Sun Kang, Mi Jin Lee, Ji Eun Lee, Hyun Wook Kim, Jin Joo Cha, Young Yoon Chung, Young Youl Hyun, Jee Young Han, Dae-Ryong Cha

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)598-607
Number of pages10
JournalLaboratory Investigation
Volume94
Issue number6
DOIs
Publication statusPublished - 2014 Jan 1

Fingerprint

Dipeptidyl-Peptidase IV Inhibitors
Ureteral Obstruction
Dipeptidyl Peptidase 4
Fibrosis
Kidney
8-epi-prostaglandin F2alpha
Exopeptidases
Incretins
Toll-Like Receptor 4
Glucagon-Like Peptide 1
Albuminuria
Cell Movement
Disease Progression
Cell Differentiation
Macrophages
LC15-0444
Hormones
Insulin
Inflammation
Food

Keywords

  • DPPIV
  • fibrosis
  • inflammation
  • LC15-0444
  • UUO

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

Cite this

Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction. / Min, Hye Sook; Kim, Jung Eun; Lee, Mi Hwa; Song, Hye Kyoung; Kang, Young Sun; Lee, Mi Jin; Lee, Ji Eun; Kim, Hyun Wook; Cha, Jin Joo; Chung, Young Yoon; Hyun, Young Youl; Han, Jee Young; Cha, Dae-Ryong.

In: Laboratory Investigation, Vol. 94, No. 6, 01.01.2014, p. 598-607.

Research output: Contribution to journalArticle

Min, Hye Sook ; Kim, Jung Eun ; Lee, Mi Hwa ; Song, Hye Kyoung ; Kang, Young Sun ; Lee, Mi Jin ; Lee, Ji Eun ; Kim, Hyun Wook ; Cha, Jin Joo ; Chung, Young Yoon ; Hyun, Young Youl ; Han, Jee Young ; Cha, Dae-Ryong. / Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction. In: Laboratory Investigation. 2014 ; Vol. 94, No. 6. pp. 598-607.
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AU - Kim, Hyun Wook

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