Dipeptidyl peptidase IV inhibitor attenuates kidney injury in rat remnant kidney

Kwon Wook Joo, Sejoong Kim, Shin Young Ahn, Ho Jun Chin, Dong Wan Chae, Jeonghwan Lee, Jin Suk Han, Ki Young Na

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Background: The inhibition of dipeptidyl peptidase (DPP) IV shows protective effects on tissue injury of the heart, lung, and kidney. Forkhead box O (FoxO) transcriptional factors regulate cellular differentiation, growth, survival, the cell cycle, metabolism, and oxidative stress. The aims of this study were to investigate whether the DPP IV inhibitor sitagliptin could attenuate kidney injury and to evaluate the status of FoxO3a signaling in the rat remnant kidney model. Methods. Rats were received two-step surgery of 5/6 renal mass reduction and fed on an oral dose of 200 mg/kg/day sitagliptin for 8 weeks. Before and after the administration of sitagliptin, physiologic parameters were measured. After 8 weeks of treatment, the kidneys were harvested. Results: The sitagliptin treatment attenuated renal dysfunction. A histological evaluation revealed that glomerulosclerosis and tubulointerstitial injury were significantly decreased by sitagliptin. Sitagliptin decreased DPP IV activity and increased the renal expression of glucagon-like peptide-1 receptor (GLP-1R). The subtotal nephrectomy led to the activation of phosphatidylinositol 3-kinase (PI3K)-Akt and FoxO3a phosphorylation, whereas sitagliptin treatment reversed these changes, resulting in PI3K-Akt pathway inactivation and FoxO3a dephosphorylation. The renal expression of catalase was increased and the phosphorylation of c-Jun N-terminal kinase (JNK) was decreased by sitagliptin. Sitagliptin treatment reduced apoptosis by decreasing cleaved caspase-3 and -9 and Bax levels and decreased macrophage infiltration. Conclusions: In rat remnant kidneys, DPP IV inhibitor attenuated renal dysfunction and structural damage. A reduction of apoptosis, inflammation and an increase of antioxidant could be suggested as a renoprotective mechanism together with the activation of FoxO3a signaling. Therefore, DPP IV inhibitors might provide a promising approach for treating CKD, but their application in clinical practice remains to be investigated.

Original languageEnglish
Article number98
JournalBMC Nephrology
Volume14
Issue number1
DOIs
Publication statusPublished - 2013 Apr 30
Externally publishedYes

Fingerprint

Dipeptidyl-Peptidase IV Inhibitors
Kidney
Wounds and Injuries
Phosphatidylinositol 3-Kinase
Dipeptidyl Peptidase 4
Phosphorylation
Heart Injuries
Apoptosis
Sitagliptin Phosphate
Caspase 9
JNK Mitogen-Activated Protein Kinases
Lung Injury
Nephrectomy
Caspase 3
Catalase
Cell Cycle
Oxidative Stress
Antioxidants
Macrophages

Keywords

  • Dipeptidyl peptidase IV
  • FoxO3a
  • Glucagon-like peptide-1 receptor
  • Kidney injury
  • Sitagliptin

ASJC Scopus subject areas

  • Nephrology

Cite this

Dipeptidyl peptidase IV inhibitor attenuates kidney injury in rat remnant kidney. / Joo, Kwon Wook; Kim, Sejoong; Ahn, Shin Young; Chin, Ho Jun; Chae, Dong Wan; Lee, Jeonghwan; Han, Jin Suk; Na, Ki Young.

In: BMC Nephrology, Vol. 14, No. 1, 98, 30.04.2013.

Research output: Contribution to journalArticle

Joo, Kwon Wook ; Kim, Sejoong ; Ahn, Shin Young ; Chin, Ho Jun ; Chae, Dong Wan ; Lee, Jeonghwan ; Han, Jin Suk ; Na, Ki Young. / Dipeptidyl peptidase IV inhibitor attenuates kidney injury in rat remnant kidney. In: BMC Nephrology. 2013 ; Vol. 14, No. 1.
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AU - Chin, Ho Jun

AU - Chae, Dong Wan

AU - Lee, Jeonghwan

AU - Han, Jin Suk

AU - Na, Ki Young

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AB - Background: The inhibition of dipeptidyl peptidase (DPP) IV shows protective effects on tissue injury of the heart, lung, and kidney. Forkhead box O (FoxO) transcriptional factors regulate cellular differentiation, growth, survival, the cell cycle, metabolism, and oxidative stress. The aims of this study were to investigate whether the DPP IV inhibitor sitagliptin could attenuate kidney injury and to evaluate the status of FoxO3a signaling in the rat remnant kidney model. Methods. Rats were received two-step surgery of 5/6 renal mass reduction and fed on an oral dose of 200 mg/kg/day sitagliptin for 8 weeks. Before and after the administration of sitagliptin, physiologic parameters were measured. After 8 weeks of treatment, the kidneys were harvested. Results: The sitagliptin treatment attenuated renal dysfunction. A histological evaluation revealed that glomerulosclerosis and tubulointerstitial injury were significantly decreased by sitagliptin. Sitagliptin decreased DPP IV activity and increased the renal expression of glucagon-like peptide-1 receptor (GLP-1R). The subtotal nephrectomy led to the activation of phosphatidylinositol 3-kinase (PI3K)-Akt and FoxO3a phosphorylation, whereas sitagliptin treatment reversed these changes, resulting in PI3K-Akt pathway inactivation and FoxO3a dephosphorylation. The renal expression of catalase was increased and the phosphorylation of c-Jun N-terminal kinase (JNK) was decreased by sitagliptin. Sitagliptin treatment reduced apoptosis by decreasing cleaved caspase-3 and -9 and Bax levels and decreased macrophage infiltration. Conclusions: In rat remnant kidneys, DPP IV inhibitor attenuated renal dysfunction and structural damage. A reduction of apoptosis, inflammation and an increase of antioxidant could be suggested as a renoprotective mechanism together with the activation of FoxO3a signaling. Therefore, DPP IV inhibitors might provide a promising approach for treating CKD, but their application in clinical practice remains to be investigated.

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