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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

Changes in protein expressions of Bcl-2 and γH2AX in kidney at 24 and 72 h after ischemia-reperfusion (IR) procedure (n = 6 at each time for each group). A and B) The protein expression of Bcl-2 at 24 h (A) and 72 h (B) after acute IR procedure. * vs. other groups with different symbols (*, †, ‡), p < 0.001 at 24 h and 72 h, respectively. C and D) The protein expression of γH2AX at 24 h (C) and 72 h (D) after acute IR procedure. * vs. other groups with different symbols (*, †, ‡), p < 0.01 at 24 h and p < 0.001 at 72 h, respectively. All statistical analyses were with one-way ANOVA followed by Bonferroni multiple comparison post hoc test. Symbols (*, †, ‡) indicate significance at the 0.05 level. SC = sham control; IR = ischemia-reperfusion; Sita = sitagliptin; Ex-4 = extendin-4.
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Figure 11: Changes in protein expressions of Bcl-2 and γH2AX in kidney at 24 and 72 h after ischemia-reperfusion (IR) procedure (n = 6 at each time for each group). A and B) The protein expression of Bcl-2 at 24 h (A) and 72 h (B) after acute IR procedure. * vs. other groups with different symbols (*, †, ‡), p < 0.001 at 24 h and 72 h, respectively. C and D) The protein expression of γH2AX at 24 h (C) and 72 h (D) after acute IR procedure. * vs. other groups with different symbols (*, †, ‡), p < 0.01 at 24 h and p < 0.001 at 72 h, respectively. All statistical analyses were with one-way ANOVA followed by Bonferroni multiple comparison post hoc test. Symbols (*, †, ‡) indicate significance at the 0.05 level. SC = sham control; IR = ischemia-reperfusion; Sita = sitagliptin; Ex-4 = extendin-4.

Mentions: The protein expressions of TNF-α, NF-κB, and ICAM-1, three indicators of inflammation, were significantly higher in group 2 than those in other groups, significantly higher in groups 3 and 4 than those in group 1 at both 24 h and 72 h after IR procedure. No significant difference in the expressions of the three parameters, however, was noted between group 3 and group 4 (Figure 7). Besides, the protein expressions of NOX-1 and NOX-2, two indices of ROS, exhibited an identical pattern compared to that of inflammatory biomarker expressions (Figure 8) among the four groups at the two time points. Furthermore, the expression of oxidized protein, an index of oxidative stress, displayed a pattern similar to that of ROS among the four groups at the two time points (Figure 9).


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)

Changes in protein expressions of Bcl-2 and γH2AX in kidney at 24 and 72 h after ischemia-reperfusion (IR) procedure (n = 6 at each time for each group). A and B) The protein expression of Bcl-2 at 24 h (A) and 72 h (B) after acute IR procedure. * vs. other groups with different symbols (*, †, ‡), p < 0.001 at 24 h and 72 h, respectively. C and D) The protein expression of γH2AX at 24 h (C) and 72 h (D) after acute IR procedure. * vs. other groups with different symbols (*, †, ‡), p < 0.01 at 24 h and p < 0.001 at 72 h, respectively. All statistical analyses were with one-way ANOVA followed by Bonferroni multiple comparison post hoc test. Symbols (*, †, ‡) indicate significance at the 0.05 level. SC = sham control; IR = ischemia-reperfusion; Sita = sitagliptin; Ex-4 = extendin-4.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 11: Changes in protein expressions of Bcl-2 and γH2AX in kidney at 24 and 72 h after ischemia-reperfusion (IR) procedure (n = 6 at each time for each group). A and B) The protein expression of Bcl-2 at 24 h (A) and 72 h (B) after acute IR procedure. * vs. other groups with different symbols (*, †, ‡), p < 0.001 at 24 h and 72 h, respectively. C and D) The protein expression of γH2AX at 24 h (C) and 72 h (D) after acute IR procedure. * vs. other groups with different symbols (*, †, ‡), p < 0.01 at 24 h and p < 0.001 at 72 h, respectively. All statistical analyses were with one-way ANOVA followed by Bonferroni multiple comparison post hoc test. Symbols (*, †, ‡) indicate significance at the 0.05 level. SC = sham control; IR = ischemia-reperfusion; Sita = sitagliptin; Ex-4 = extendin-4.
Mentions: The protein expressions of TNF-α, NF-κB, and ICAM-1, three indicators of inflammation, were significantly higher in group 2 than those in other groups, significantly higher in groups 3 and 4 than those in group 1 at both 24 h and 72 h after IR procedure. No significant difference in the expressions of the three parameters, however, was noted between group 3 and group 4 (Figure 7). Besides, the protein expressions of NOX-1 and NOX-2, two indices of ROS, exhibited an identical pattern compared to that of inflammatory biomarker expressions (Figure 8) among the four groups at the two time points. Furthermore, the expression of oxidized protein, an index of oxidative stress, displayed a pattern similar to that of ROS among the four groups at the two time points (Figure 9).

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