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Exendin-4 and sitagliptin protect kidney from ischemia-reperfusion injury through suppressing oxidative stress and inflammatory reaction.

Chen YT, Tsai TH, Yang CC, Sun CK, Chang LT, Chen HH, Chang CL, Sung PH, Zhen YY, Leu S, Chang HW, Chen YL, Yip HK - J Transl Med (2013)

Bottom Line: Expressions of oxidized protein, reactive oxygen species (NOX-1, NOX-2), apoptosis (Bax, caspase-3 and PARP), and DNA damage marker (γH2AX+) of IR kidney at 24 and 72 hrs exhibited a pattern similar to that of inflammatory mediators among all groups (all p < 0.01).Renal expression of glucagon-like peptide-1 receptor, and anti-oxidant biomarkers at cellular (GPx, GR) and protein (NQO-1, HO-1, GPx) levels at 24 and 72 hr were lowest in group 1, significantly lower in group 2 than in groups 3 and 4 (all p < 0.01).Exendin-4 and sitagliptin provided significant protection for the kidneys against acute IR injury.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123, Dapi Road, Niaosung Dist,, Kaohsiung city 83301, Taiwan. han.gung@msa.hinet.net.

ABSTRACT

Background: This study tested the hypothesis that exendin-4 and sitagliptin can effectively protect kidney from acute ischemia-reperfusion (IR) injury.

Methods: Adult SD-rats (n = 48) equally divided into group 1 (sham control), group 2 (IR injury), group 3 [IR + sitagliptin 600 mg/kg at post-IR 1, 24, 48 hr)], and group 4 [IR + exendin-4 10 μm/kg at 1 hr after procedure] were sacrificed after 24 and 72 hrs (n = 6 at each time from each group) following clamping of bilateral renal pedicles for 60 minutes (groups 2-4).

Results: Serum creatinine level and urine protein to creatinine ratio were highest in group 2 and lowest in group 1 (all p < 0.001) without notable differences between groups 3 and 4. Kidney injury score, expressions of inflammatory biomarkers at mRNA (MMP-9, TNF-α, IL-1β, PAI-1), protein (TNF-α, NF-κB and VCAM-1), and cellular (CD68+) levels in injured kidneys at 24 and 72 hr showed an identical pattern compared to that of creatinine level in all groups (all p < 0.0001). Expressions of oxidized protein, reactive oxygen species (NOX-1, NOX-2), apoptosis (Bax, caspase-3 and PARP), and DNA damage marker (γH2AX+) of IR kidney at 24 and 72 hrs exhibited a pattern similar to that of inflammatory mediators among all groups (all p < 0.01). Renal expression of glucagon-like peptide-1 receptor, and anti-oxidant biomarkers at cellular (GPx, GR) and protein (NQO-1, HO-1, GPx) levels at 24 and 72 hr were lowest in group 1, significantly lower in group 2 than in groups 3 and 4 (all p < 0.01).

Conclusion: Exendin-4 and sitagliptin provided significant protection for the kidneys against acute IR injury.

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Related in: MedlinePlus

Immunohistochemical (IHC) and H.E. staining and Western blot for determining the impact of sitagliptin and exendin-9-39 effect on acute kidney ischemia-reperfusion (IR) injury at 24 h after IR procedure. A to D) The H.E stain (200 x) showing notably higher acute kidney injury score, including: brush border in renal tubules (yellow arrowheads), cast formation (green asterisk), tubular dilatation (blue asterisk), tubular necrosis (green arrows), and dilatation of Bowman’s capsule (blue arrows) in ischemia reperfusion (IR) only and IR + sitagliptin (Sita) + exendin (Ex)-9-39 animals than in IR + sitagliptin animals. E to H) The immunohistochemical (IHC) stain (200 x) demonstrating higher expression of glucagon-like peptide-1 receptor (GLP-1R) (brown color staining) in IR animals with sitagliptin + exendin-9-39 treatment and further higher expression of this biomarker than in RI only animals in renal parenchyma. Very few expression of GLP-1R in normal kidney parenchyma (E) was observed. Scale bars in right lower corner represent 50 μm. I) The protein expressions of ADPH oxidase (NOX)-1, NOX-2, intercellular adhesion molecule (ICAM)-1, tumor necrotic factor (TNF)-α, nuclear factor (NF)- κB, matrix metalloproteinase (MMP)-9, and J) oxidized protein were remarkably higher in IR and IR + sitagliptin + exendin-9-39 animals than in IR + sitagliptin animals.
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Figure 1: Immunohistochemical (IHC) and H.E. staining and Western blot for determining the impact of sitagliptin and exendin-9-39 effect on acute kidney ischemia-reperfusion (IR) injury at 24 h after IR procedure. A to D) The H.E stain (200 x) showing notably higher acute kidney injury score, including: brush border in renal tubules (yellow arrowheads), cast formation (green asterisk), tubular dilatation (blue asterisk), tubular necrosis (green arrows), and dilatation of Bowman’s capsule (blue arrows) in ischemia reperfusion (IR) only and IR + sitagliptin (Sita) + exendin (Ex)-9-39 animals than in IR + sitagliptin animals. E to H) The immunohistochemical (IHC) stain (200 x) demonstrating higher expression of glucagon-like peptide-1 receptor (GLP-1R) (brown color staining) in IR animals with sitagliptin + exendin-9-39 treatment and further higher expression of this biomarker than in RI only animals in renal parenchyma. Very few expression of GLP-1R in normal kidney parenchyma (E) was observed. Scale bars in right lower corner represent 50 μm. I) The protein expressions of ADPH oxidase (NOX)-1, NOX-2, intercellular adhesion molecule (ICAM)-1, tumor necrotic factor (TNF)-α, nuclear factor (NF)- κB, matrix metalloproteinase (MMP)-9, and J) oxidized protein were remarkably higher in IR and IR + sitagliptin + exendin-9-39 animals than in IR + sitagliptin animals.

Mentions: To elucidate the possible GLP-1-mediated therapeutic effect of sitagliptin against acute kidney IR injury, the circulating level of GLP-1 was measured in each animal. In addition, eight additional SD rats were equally divided into: 1) sham control, 2) IR only, 3) IR + sitagliptin 600 mg/kg (orally, 1 hr after acute kidney IR), 4) IR + sitagliptin 600 mg/kg + exendin-9-39 (an inhibitor of exendin-4) 10 μm/kg at 1 hr after the procedure. The animals were sacrificed at 24 hr after acute kidney IR. The kidney was collected in each animals for specific study (please see the results of Figure 1).


Exendin-4 and sitagliptin protect kidney from ischemia-reperfusion injury through suppressing oxidative stress and inflammatory reaction.

Chen YT, Tsai TH, Yang CC, Sun CK, Chang LT, Chen HH, Chang CL, Sung PH, Zhen YY, Leu S, Chang HW, Chen YL, Yip HK - J Transl Med (2013)

Immunohistochemical (IHC) and H.E. staining and Western blot for determining the impact of sitagliptin and exendin-9-39 effect on acute kidney ischemia-reperfusion (IR) injury at 24 h after IR procedure. A to D) The H.E stain (200 x) showing notably higher acute kidney injury score, including: brush border in renal tubules (yellow arrowheads), cast formation (green asterisk), tubular dilatation (blue asterisk), tubular necrosis (green arrows), and dilatation of Bowman’s capsule (blue arrows) in ischemia reperfusion (IR) only and IR + sitagliptin (Sita) + exendin (Ex)-9-39 animals than in IR + sitagliptin animals. E to H) The immunohistochemical (IHC) stain (200 x) demonstrating higher expression of glucagon-like peptide-1 receptor (GLP-1R) (brown color staining) in IR animals with sitagliptin + exendin-9-39 treatment and further higher expression of this biomarker than in RI only animals in renal parenchyma. Very few expression of GLP-1R in normal kidney parenchyma (E) was observed. Scale bars in right lower corner represent 50 μm. I) The protein expressions of ADPH oxidase (NOX)-1, NOX-2, intercellular adhesion molecule (ICAM)-1, tumor necrotic factor (TNF)-α, nuclear factor (NF)- κB, matrix metalloproteinase (MMP)-9, and J) oxidized protein were remarkably higher in IR and IR + sitagliptin + exendin-9-39 animals than in IR + sitagliptin animals.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4231365&req=5

Figure 1: Immunohistochemical (IHC) and H.E. staining and Western blot for determining the impact of sitagliptin and exendin-9-39 effect on acute kidney ischemia-reperfusion (IR) injury at 24 h after IR procedure. A to D) The H.E stain (200 x) showing notably higher acute kidney injury score, including: brush border in renal tubules (yellow arrowheads), cast formation (green asterisk), tubular dilatation (blue asterisk), tubular necrosis (green arrows), and dilatation of Bowman’s capsule (blue arrows) in ischemia reperfusion (IR) only and IR + sitagliptin (Sita) + exendin (Ex)-9-39 animals than in IR + sitagliptin animals. E to H) The immunohistochemical (IHC) stain (200 x) demonstrating higher expression of glucagon-like peptide-1 receptor (GLP-1R) (brown color staining) in IR animals with sitagliptin + exendin-9-39 treatment and further higher expression of this biomarker than in RI only animals in renal parenchyma. Very few expression of GLP-1R in normal kidney parenchyma (E) was observed. Scale bars in right lower corner represent 50 μm. I) The protein expressions of ADPH oxidase (NOX)-1, NOX-2, intercellular adhesion molecule (ICAM)-1, tumor necrotic factor (TNF)-α, nuclear factor (NF)- κB, matrix metalloproteinase (MMP)-9, and J) oxidized protein were remarkably higher in IR and IR + sitagliptin + exendin-9-39 animals than in IR + sitagliptin animals.
Mentions: To elucidate the possible GLP-1-mediated therapeutic effect of sitagliptin against acute kidney IR injury, the circulating level of GLP-1 was measured in each animal. In addition, eight additional SD rats were equally divided into: 1) sham control, 2) IR only, 3) IR + sitagliptin 600 mg/kg (orally, 1 hr after acute kidney IR), 4) IR + sitagliptin 600 mg/kg + exendin-9-39 (an inhibitor of exendin-4) 10 μm/kg at 1 hr after the procedure. The animals were sacrificed at 24 hr after acute kidney IR. The kidney was collected in each animals for specific study (please see the results of Figure 1).

Bottom Line: Expressions of oxidized protein, reactive oxygen species (NOX-1, NOX-2), apoptosis (Bax, caspase-3 and PARP), and DNA damage marker (γH2AX+) of IR kidney at 24 and 72 hrs exhibited a pattern similar to that of inflammatory mediators among all groups (all p < 0.01).Renal expression of glucagon-like peptide-1 receptor, and anti-oxidant biomarkers at cellular (GPx, GR) and protein (NQO-1, HO-1, GPx) levels at 24 and 72 hr were lowest in group 1, significantly lower in group 2 than in groups 3 and 4 (all p < 0.01).Exendin-4 and sitagliptin provided significant protection for the kidneys against acute IR injury.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123, Dapi Road, Niaosung Dist,, Kaohsiung city 83301, Taiwan. han.gung@msa.hinet.net.

ABSTRACT

Background: This study tested the hypothesis that exendin-4 and sitagliptin can effectively protect kidney from acute ischemia-reperfusion (IR) injury.

Methods: Adult SD-rats (n = 48) equally divided into group 1 (sham control), group 2 (IR injury), group 3 [IR + sitagliptin 600 mg/kg at post-IR 1, 24, 48 hr)], and group 4 [IR + exendin-4 10 μm/kg at 1 hr after procedure] were sacrificed after 24 and 72 hrs (n = 6 at each time from each group) following clamping of bilateral renal pedicles for 60 minutes (groups 2-4).

Results: Serum creatinine level and urine protein to creatinine ratio were highest in group 2 and lowest in group 1 (all p < 0.001) without notable differences between groups 3 and 4. Kidney injury score, expressions of inflammatory biomarkers at mRNA (MMP-9, TNF-α, IL-1β, PAI-1), protein (TNF-α, NF-κB and VCAM-1), and cellular (CD68+) levels in injured kidneys at 24 and 72 hr showed an identical pattern compared to that of creatinine level in all groups (all p < 0.0001). Expressions of oxidized protein, reactive oxygen species (NOX-1, NOX-2), apoptosis (Bax, caspase-3 and PARP), and DNA damage marker (γH2AX+) of IR kidney at 24 and 72 hrs exhibited a pattern similar to that of inflammatory mediators among all groups (all p < 0.01). Renal expression of glucagon-like peptide-1 receptor, and anti-oxidant biomarkers at cellular (GPx, GR) and protein (NQO-1, HO-1, GPx) levels at 24 and 72 hr were lowest in group 1, significantly lower in group 2 than in groups 3 and 4 (all p < 0.01).

Conclusion: Exendin-4 and sitagliptin provided significant protection for the kidneys against acute IR injury.

Show MeSH
Related in: MedlinePlus