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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

The gene expressions of inflammatory and anti-inflammatory biomarkers at 72 h after ischemia-reperfusion (IR) procedure (n = 6 at each time for each group). A to C) The mRNA expressions of tumor necrotic factor (TNF)-α (A), matrix metalloproteinase (MMP)-9 (B) and interleukin (IL)-β (C); * vs. other groups with different symbols (*, †, ‡, §), p < 0.001. D) The mRNA expression of plasminogen activator inhibitor (PAI)-1; * vs. other groups with different symbols (*, †, ‡, §), p < 0.0001. E to F) The mRNA expressions of endothelial nitric oxide synthase (eNOS) and IL-10; * vs. other groups with different symbols (*, †, ‡, §), p < 0.001. All statistical analyses using one-way ANOVA, followed by Bonferroni multiple comparison post hoc test (n = 6). Symbols (*, †, ‡, §) indicate significance (at 0.05 level). SC = sham control; IR = ischemia-reperfusion; Sita = sitagliptin; Ex-4 = extendin-4.
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Figure 4: The gene expressions of inflammatory and anti-inflammatory biomarkers at 72 h after ischemia-reperfusion (IR) procedure (n = 6 at each time for each group). A to C) The mRNA expressions of tumor necrotic factor (TNF)-α (A), matrix metalloproteinase (MMP)-9 (B) and interleukin (IL)-β (C); * vs. other groups with different symbols (*, †, ‡, §), p < 0.001. D) The mRNA expression of plasminogen activator inhibitor (PAI)-1; * vs. other groups with different symbols (*, †, ‡, §), p < 0.0001. E to F) The mRNA expressions of endothelial nitric oxide synthase (eNOS) and IL-10; * vs. other groups with different symbols (*, †, ‡, §), p < 0.001. All statistical analyses using one-way ANOVA, followed by Bonferroni multiple comparison post hoc test (n = 6). Symbols (*, †, ‡, §) indicate significance (at 0.05 level). SC = sham control; IR = ischemia-reperfusion; Sita = sitagliptin; Ex-4 = extendin-4.

Mentions: To evaluate the therapeutic impact of sitagliptin and exendin-4 on IR-induced renal injury, histological scoring based on the typical microscopic features of acute tubular damage, including extensive tubular necrosis and dilatation, as well as cast formation and loss of brush border was adopted. The injury was found to be significantly higher in group 2 than in other groups, significantly higher in groups 3 and 4 than in group 1 (Figure 3A-E), and significantly higher in group 3 than group 4 at 24 h or 72 h after IR procedure (Figure 3F-J). These pathological findings might suggest that on dose of exendin-4 was not inferior to sitagliptin therapy for protecting acute kidney IR injury.


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)

The gene expressions of inflammatory and anti-inflammatory biomarkers at 72 h after ischemia-reperfusion (IR) procedure (n = 6 at each time for each group). A to C) The mRNA expressions of tumor necrotic factor (TNF)-α (A), matrix metalloproteinase (MMP)-9 (B) and interleukin (IL)-β (C); * vs. other groups with different symbols (*, †, ‡, §), p < 0.001. D) The mRNA expression of plasminogen activator inhibitor (PAI)-1; * vs. other groups with different symbols (*, †, ‡, §), p < 0.0001. E to F) The mRNA expressions of endothelial nitric oxide synthase (eNOS) and IL-10; * vs. other groups with different symbols (*, †, ‡, §), p < 0.001. All statistical analyses using one-way ANOVA, followed by Bonferroni multiple comparison post hoc test (n = 6). Symbols (*, †, ‡, §) indicate significance (at 0.05 level). SC = sham control; IR = ischemia-reperfusion; Sita = sitagliptin; Ex-4 = extendin-4.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: The gene expressions of inflammatory and anti-inflammatory biomarkers at 72 h after ischemia-reperfusion (IR) procedure (n = 6 at each time for each group). A to C) The mRNA expressions of tumor necrotic factor (TNF)-α (A), matrix metalloproteinase (MMP)-9 (B) and interleukin (IL)-β (C); * vs. other groups with different symbols (*, †, ‡, §), p < 0.001. D) The mRNA expression of plasminogen activator inhibitor (PAI)-1; * vs. other groups with different symbols (*, †, ‡, §), p < 0.0001. E to F) The mRNA expressions of endothelial nitric oxide synthase (eNOS) and IL-10; * vs. other groups with different symbols (*, †, ‡, §), p < 0.001. All statistical analyses using one-way ANOVA, followed by Bonferroni multiple comparison post hoc test (n = 6). Symbols (*, †, ‡, §) indicate significance (at 0.05 level). SC = sham control; IR = ischemia-reperfusion; Sita = sitagliptin; Ex-4 = extendin-4.
Mentions: To evaluate the therapeutic impact of sitagliptin and exendin-4 on IR-induced renal injury, histological scoring based on the typical microscopic features of acute tubular damage, including extensive tubular necrosis and dilatation, as well as cast formation and loss of brush border was adopted. The injury was found to be significantly higher in group 2 than in other groups, significantly higher in groups 3 and 4 than in group 1 (Figure 3A-E), and significantly higher in group 3 than group 4 at 24 h or 72 h after IR procedure (Figure 3F-J). These pathological findings might suggest that on dose of exendin-4 was not inferior to sitagliptin therapy for protecting acute kidney IR injury.

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