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

被引：57

作者：

Chang, Meng-wei ^{[1
]}

Chen, Chih-hung ^{[2
]}

Chen, Yi-ching ^{[3
]}

Wu, Ying-chun ^{[3
]}

Zhen, Yen-yi ^{[3
]}

Leu, Steve ^{[4
]}

Tsai, Tzu-hsien ^{[3
]}

Ko, Sheung-fat ^{[5
]}

Sung, Pei-hsun ^{[3
]}

Yang, Chih-chau ^{[6
]}

Chiang, Hsin-ju ^{[7
]}

Chang, Hsueh-wen ^{[9
]}

Chen, Yen-ta ^{[8
]}

Yip, Hon-kan ^{[3
,4
]}

机构：

[1] Kaohsiung Chang Gung Mem Hosp, Dept Emergency Med, Kaohsiung, Taiwan

[2] Kaohsiung Chang Gung Mem Hosp, Div Gen Med, Kaohsiung, Taiwan

[3] Kaohsiung Chang Gung Mem Hosp, Dept Internal Med, Div Cardiol, Kaohsiung, Taiwan

[4] Kaohsiung Chang Gung Mem Hosp, Ctr Translat Res Biomed Sci, Kaohsiung, Taiwan

[5] Kaohsiung Chang Gung Mem Hosp, Dept Radiol, Kaohsiung, Taiwan

[6] Kaohsiung Chang Gung Mem Hosp, Dept Internal Med, Div Nephrol, Kaohsiung, Taiwan

[7] Kaohsiung Chang Gung Mem Hosp, Dept Obstet & Gynecol, Kaohsiung, Taiwan

[8] Kaohsiung Chang Gung Mem Hosp, Dept Surg, Div Urol, Kaohsiung, Taiwan

[9] Natl Sun Yat Sen Univ, Dept Biol Sci, Kaohsiung 80424, Taiwan

来源：

ACTA PHARMACOLOGICA SINICA | 2015年 / 36卷 / 01期

关键词：

sitagliptin; chronic kidney disease; ischemia reperfusion injury; inflammation; oxidative stress; reactive oxygen species; apoptosis; angiogenesis; GLP-1; DIPEPTIDYL PEPTIDASE-4 INHIBITOR; ACUTE-RENAL-FAILURE; MORTALITY; CELLS; THERAPY; DISEASE;

D O I：

10.1038/aps.2014.98

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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-alpha and NF-kappa B) 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-1a+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.

引用

页码：119 / 130

页数：12

共 32 条

[11] The Oral Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Increases Circulating Endothelial Progenitor Cells in Patients With Type 2 Diabetes Possible role of stromal-derived factor-1α [J].

Fadini, Gian Paolo ;

Boscaro, Elisa ;

Albiero, Mattia ;

Menegazzo, Lisa ;

Frison, Vera ;

de Kreutzenberg, Saula ;

Agostini, Carlo ;

Tiengo, Antonio ;

Avogaro, Angelo .

DIABETES CARE, 2010, 33 (07) :1607-1609

[12] Acute Kidney Injury in a Chinese Hospitalized Population [J].

Fang, Yi ;

Ding, Xiaoqiang ;

Zhong, Yihong ;

Zou, Jianzhou ;

Teng, Jie ;

Tang, Ying ;

Lin, Jing ;

Lin, Pan .

BLOOD PURIFICATION, 2010, 30 (02) :120-126

[13] ESRD patients in 2004: global overview of patient numbers, treatment modalities and associated trends [J].

Grassmann, A ;

Gioberge, S ;

Moeller, S ;

Brown, G .

NEPHROLOGY DIALYSIS TRANSPLANTATION, 2005, 20 (12) :2587-2593

[14] Dipeptidyl peptidase-4 inhibitor improves neovascularization by increasing circulating endothelial progenitor cells [J].

Huang, Chun-Yao ;

Shih, Chun-Ming ;

Tsao, Nai-Wen ;

Lin, Yi-Wen ;

Huang, Po-Hsun ;

Wu, Shinn-Chih ;

Lee, Ai-Wei ;

Kao, Yung-Ta ;

Chang, Nen-Chung ;

Nakagami, Hironori ;

Morishita, Ryuichi ;

Ou, Keng-Liang ;

Hou, Wen-Chi ;

Lin, Cheng-Yen ;

Shyu, Kuo-Gi ;

Lin, Feng-Yen .

BRITISH JOURNAL OF PHARMACOLOGY, 2012, 167 (07) :1506-1519

[15] Impact of Sitagliptin on Carotid Intima-Media Thickness in Patients With Coronary Artery Disease and Impaired Glucose Tolerance or Mild Diabetes Mellitus [J].

Ishikawa, Shinji ;

Shimano, Masayuki ;

Watarai, Masato ;

Koyasu, Masayoshi ;

Uchikawa, Tomohiro ;

Ishii, Hideki ;

Inden, Yasuya ;

Takemoto, Kenji ;

Murohara, Toyoaki .

AMERICAN JOURNAL OF CARDIOLOGY, 2014, 114 (03) :384-388

[16] Changes in survival among elderly patients initiating dialysis from 1990 to 1999 [J].

Jassal, Sarbjit Vanita ;

Trpeski, Lilyanna ;

Zhu, Naisu ;

Fenton, Stanley ;

Hemmelgarn, Brenda .

CANADIAN MEDICAL ASSOCIATION JOURNAL, 2007, 177 (09) :1033-1038

[17] Acute Kidney Injury Associates with Increased Long-Term Mortality [J].

Lafrance, Jean-Philippe ;

Miller, Donald R. .

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2010, 21 (02) :345-352

[18]

Lameire N, 2005, LANCET, V365, P417

[19] The effect of acute renal failure on mortality - A cohort analysis [J].

Levy, EM ;

Viscoli, CM ;

Horwitz, RI .

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 1996, 275 (19) :1489-1494

[20] Mobilized Human Hematopoietic Stem/Progenitor Cells Promote Kidney Repair After Ischemia/Reperfusion Injury [J].

Li, Bing ;

Cohen, Amy ;

Hudson, Thomas E. ;

Motlagh, Delara ;

Amrani, David L. ;

Duffield, Jeremy S. .

CIRCULATION, 2010, 121 (20) :2211-2220

← 1 2 3 4 →