Sitagliptin protects rat kidneys from acute ischemia-reperfusion injury via upregulation of GLP-1 and GLP-1 receptors

Meng Wei Chang; Chih Hung Chen; Yi Ching Chen; Ying Chun Wu; Yen Yi Zhen; Steve Leu; Tzu Hsien Tsai; Sheung Fat Ko; Pei Hsun Sung; Chih Chau Yang; Hsin Ju Chiang; Hsueh Wen Chang; Yen Ta Chen; Hon Kan Yip

doi:10.1038/aps.2014.98

Sitagliptin protects rat kidneys from acute ischemia-reperfusion injury via upregulation of GLP-1 and GLP-1 receptors

Meng Wei Chang, Chih Hung Chen, Yi Ching Chen, Ying Chun Wu, Yen Yi Zhen, Steve Leu, Tzu Hsien Tsai, Sheung Fat Ko, Pei Hsun Sung, Chih Chau Yang, Hsin Ju Chiang, Hsueh Wen Chang, Yen Ta Chen, Hon Kan Yip^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal Article › peer-review

56 Scopus citations

Abstract

Aim:Sitagliptin, an oral glucose-lowering agent, has been found to produce cardiovascular protection possibly via anti-inflammatory and anti-atherosclerotic activities of glucagon-like peptide-1 receptor (GLP-1). The aim of this study was to investigate whether sitagliptin protected the kidney function from acute ischemia-reperfusion (IR) injury in rats.

Methods:Adult male SD rats were categorized into 4 groups: sham control, IR injury, IR+sitagliptin (300 mg/kg) and IR+sitagliptin (600 mg/kg). Acute renal IR injury of both kidneys was induced by clamping the renal pedicles for 1 h. The drug was orally administered at 1, 24 and 48 h after acute IR. Blood samples and 24-h urine were collected before and at 72 h after acute IR. Then the rats were sacrificed, and the kidneys were harvested for biochemical and immunohistochemical studies.

Results:Acute IR procedure markedly increased serum levels of creatinine and BUN and the ratio of urine protein to creatinine. The kidney injury score, inflammatory biomarkers (MMP-9, TNF-α and NF-κB) levels and CD68+ cells in IR kidneys were considerably increased. The expression of oxidized protein, reactive oxygen species (NOX-1, NOX-2) and apoptosis proteins (Bax, caspase-3, PARP) in IR kidneys was also significantly upregulated. All these pathological changes were suppressed by sitagliptin in a dose-dependent manner. Furthermore, the serum GLP-1 level, and the expression of GLP-1 receptor, anti-oxidant biomarkers (HO-1 and NQO-1 cells, as well as SOD-1, NQO-1 and HO-1 proteins), and angiogenesis markers (SDF-1α+ and CXCR4+ cells) in IR kidneys were significantly increased, and further upregulated by sitagliptin.

Conclusion:Sitagliptin dose-dependently protects rat kidneys from acute IR injury via upregulation of serum GLP-1 and GLP-1 receptor expression in kidneys.

Original language	English
Pages (from-to)	119-130
Number of pages	12
Journal	Acta Pharmacologica Sinica
Volume	36
Issue number	1
DOIs	https://doi.org/10.1038/aps.2014.98
State	Published - 01 2015

Bibliographical note

Publisher Copyright:
© 2015 CPS and SIMM.

Keywords

GLP-1
angiogenesis
apoptosis
chronic kidney disease
inflammation
ischemia reperfusion injury
oxidative stress
reactive oxygen species
sitagliptin

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Chang, M. W., Chen, C. H., Chen, Y. C., Wu, Y. C., Zhen, Y. Y., Leu, S., Tsai, T. H., Ko, S. F., Sung, P. H., Yang, C. C., Chiang, H. J., Chang, H. W., Chen, Y. T., & Yip, H. K. (2015). Sitagliptin protects rat kidneys from acute ischemia-reperfusion injury via upregulation of GLP-1 and GLP-1 receptors. Acta Pharmacologica Sinica, 36(1), 119-130. https://doi.org/10.1038/aps.2014.98

@article{739bab28df394a159467620d4edafd63,

title = "Sitagliptin protects rat kidneys from acute ischemia-reperfusion injury via upregulation of GLP-1 and GLP-1 receptors",

abstract = "Aim:Sitagliptin, an oral glucose-lowering agent, has been found to produce cardiovascular protection possibly via anti-inflammatory and anti-atherosclerotic activities of glucagon-like peptide-1 receptor (GLP-1). The aim of this study was to investigate whether sitagliptin protected the kidney function from acute ischemia-reperfusion (IR) injury in rats.Methods:Adult male SD rats were categorized into 4 groups: sham control, IR injury, IR+sitagliptin (300 mg/kg) and IR+sitagliptin (600 mg/kg). Acute renal IR injury of both kidneys was induced by clamping the renal pedicles for 1 h. The drug was orally administered at 1, 24 and 48 h after acute IR. Blood samples and 24-h urine were collected before and at 72 h after acute IR. Then the rats were sacrificed, and the kidneys were harvested for biochemical and immunohistochemical studies.Results:Acute IR procedure markedly increased serum levels of creatinine and BUN and the ratio of urine protein to creatinine. The kidney injury score, inflammatory biomarkers (MMP-9, TNF-α and NF-κB) levels and CD68+ cells in IR kidneys were considerably increased. The expression of oxidized protein, reactive oxygen species (NOX-1, NOX-2) and apoptosis proteins (Bax, caspase-3, PARP) in IR kidneys was also significantly upregulated. All these pathological changes were suppressed by sitagliptin in a dose-dependent manner. Furthermore, the serum GLP-1 level, and the expression of GLP-1 receptor, anti-oxidant biomarkers (HO-1 and NQO-1 cells, as well as SOD-1, NQO-1 and HO-1 proteins), and angiogenesis markers (SDF-1α+ and CXCR4+ cells) in IR kidneys were significantly increased, and further upregulated by sitagliptin.Conclusion:Sitagliptin dose-dependently protects rat kidneys from acute IR injury via upregulation of serum GLP-1 and GLP-1 receptor expression in kidneys.",

keywords = "GLP-1, angiogenesis, apoptosis, chronic kidney disease, inflammation, ischemia reperfusion injury, oxidative stress, reactive oxygen species, sitagliptin",

author = "Chang, {Meng Wei} and Chen, {Chih Hung} and Chen, {Yi Ching} and Wu, {Ying Chun} and Zhen, {Yen Yi} and Steve Leu and Tsai, {Tzu Hsien} and Ko, {Sheung Fat} and Sung, {Pei Hsun} and Yang, {Chih Chau} and Chiang, {Hsin Ju} and Chang, {Hsueh Wen} and Chen, {Yen Ta} and Yip, {Hon Kan}",

note = "Publisher Copyright: {\textcopyright} 2015 CPS and SIMM.",

year = "2015",

month = jan,

doi = "10.1038/aps.2014.98",

language = "英语",

volume = "36",

pages = "119--130",

journal = "Acta Pharmacologica Sinica",

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T1 - Sitagliptin protects rat kidneys from acute ischemia-reperfusion injury via upregulation of GLP-1 and GLP-1 receptors

AU - Chang, Meng Wei

AU - Chen, Chih Hung

AU - Chen, Yi Ching

AU - Wu, Ying Chun

AU - Zhen, Yen Yi

AU - Leu, Steve

AU - Tsai, Tzu Hsien

AU - Ko, Sheung Fat

AU - Sung, Pei Hsun

AU - Yang, Chih Chau

AU - Chiang, Hsin Ju

AU - Chang, Hsueh Wen

AU - Chen, Yen Ta

AU - Yip, Hon Kan

PY - 2015/1

Y1 - 2015/1

N2 - Aim:Sitagliptin, an oral glucose-lowering agent, has been found to produce cardiovascular protection possibly via anti-inflammatory and anti-atherosclerotic activities of glucagon-like peptide-1 receptor (GLP-1). The aim of this study was to investigate whether sitagliptin protected the kidney function from acute ischemia-reperfusion (IR) injury in rats.Methods:Adult male SD rats were categorized into 4 groups: sham control, IR injury, IR+sitagliptin (300 mg/kg) and IR+sitagliptin (600 mg/kg). Acute renal IR injury of both kidneys was induced by clamping the renal pedicles for 1 h. The drug was orally administered at 1, 24 and 48 h after acute IR. Blood samples and 24-h urine were collected before and at 72 h after acute IR. Then the rats were sacrificed, and the kidneys were harvested for biochemical and immunohistochemical studies.Results:Acute IR procedure markedly increased serum levels of creatinine and BUN and the ratio of urine protein to creatinine. The kidney injury score, inflammatory biomarkers (MMP-9, TNF-α and NF-κB) levels and CD68+ cells in IR kidneys were considerably increased. The expression of oxidized protein, reactive oxygen species (NOX-1, NOX-2) and apoptosis proteins (Bax, caspase-3, PARP) in IR kidneys was also significantly upregulated. All these pathological changes were suppressed by sitagliptin in a dose-dependent manner. Furthermore, the serum GLP-1 level, and the expression of GLP-1 receptor, anti-oxidant biomarkers (HO-1 and NQO-1 cells, as well as SOD-1, NQO-1 and HO-1 proteins), and angiogenesis markers (SDF-1α+ and CXCR4+ cells) in IR kidneys were significantly increased, and further upregulated by sitagliptin.Conclusion:Sitagliptin dose-dependently protects rat kidneys from acute IR injury via upregulation of serum GLP-1 and GLP-1 receptor expression in kidneys.

AB - Aim:Sitagliptin, an oral glucose-lowering agent, has been found to produce cardiovascular protection possibly via anti-inflammatory and anti-atherosclerotic activities of glucagon-like peptide-1 receptor (GLP-1). The aim of this study was to investigate whether sitagliptin protected the kidney function from acute ischemia-reperfusion (IR) injury in rats.Methods:Adult male SD rats were categorized into 4 groups: sham control, IR injury, IR+sitagliptin (300 mg/kg) and IR+sitagliptin (600 mg/kg). Acute renal IR injury of both kidneys was induced by clamping the renal pedicles for 1 h. The drug was orally administered at 1, 24 and 48 h after acute IR. Blood samples and 24-h urine were collected before and at 72 h after acute IR. Then the rats were sacrificed, and the kidneys were harvested for biochemical and immunohistochemical studies.Results:Acute IR procedure markedly increased serum levels of creatinine and BUN and the ratio of urine protein to creatinine. The kidney injury score, inflammatory biomarkers (MMP-9, TNF-α and NF-κB) levels and CD68+ cells in IR kidneys were considerably increased. The expression of oxidized protein, reactive oxygen species (NOX-1, NOX-2) and apoptosis proteins (Bax, caspase-3, PARP) in IR kidneys was also significantly upregulated. All these pathological changes were suppressed by sitagliptin in a dose-dependent manner. Furthermore, the serum GLP-1 level, and the expression of GLP-1 receptor, anti-oxidant biomarkers (HO-1 and NQO-1 cells, as well as SOD-1, NQO-1 and HO-1 proteins), and angiogenesis markers (SDF-1α+ and CXCR4+ cells) in IR kidneys were significantly increased, and further upregulated by sitagliptin.Conclusion:Sitagliptin dose-dependently protects rat kidneys from acute IR injury via upregulation of serum GLP-1 and GLP-1 receptor expression in kidneys.

KW - GLP-1

KW - angiogenesis

KW - apoptosis

KW - chronic kidney disease

KW - inflammation

KW - ischemia reperfusion injury

KW - oxidative stress

KW - reactive oxygen species

KW - sitagliptin

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SN - 1671-4083

VL - 36

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JO - Acta Pharmacologica Sinica

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IS - 1

ER -

Sitagliptin protects rat kidneys from acute ischemia-reperfusion injury via upregulation of GLP-1 and GLP-1 receptors

Abstract

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Keywords

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