Exendin-4 and sitagliptin protect kidney from ischemia-reperfusion injury through suppressing oxidative stress and infla
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RESEARCH
Open Access
Exendin-4 and sitagliptin protect kidney from ischemia-reperfusion injury through suppressing oxidative stress and inflammatory reaction Yen-Ta Chen1, Tzu-Hsien Tsai2, Chih-Chau Yang3, Cheuk-Kwan Sun4, Li-Teh Chang5, Hung-Hwa Chen6, Chia-Lo Chang6, Pei-Hsun Sung2, Yen-Yi Zhen2, Steve Leu7, Hsueh-Wen Chang8, Yung-Lung Chen2 and Hon-Kan Yip2,7*
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. Keywords: Exendin-4, Sitagliptin, Acute ischemia-reperfusion injury, Inflammation, Oxidative stress
Background Acute kidney injury (AKI) is a commonly encountered complication in hospitalized patients and significantly contributes to morbidity and mortality [1-5]. Recent studies have further demonstrated that AKI was evident in around 20% of patients who died in hospitals and up to 50% of patients in the intensive care unit (ICU) [6,7]. The * Correspondence: [email protected] 2 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 7 Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan Full list of author information is available at the end of the article
etiology of AKI is multifactorial [1-12]. Among the various etiologies of hospital-acquired AKI, ischemia-reperfusion (IR) injury is
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