Abstract
BackgroundThis study tested the hypothesis that exendin-4 and sitagliptin can effectively protect kidney from acute ischemia-reperfusion (IR) injury.MethodsAdult 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).ResultsSerum 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).ConclusionExendin-4 and sitagliptin provided significant protection for the kidneys against acute IR injury.
Highlights
This study tested the hypothesis that exendin-4 and sitagliptin can effectively protect kidney from acute ischemia-reperfusion (IR) injury
It is rational to hypothesize that the inflammatory reaction and oxidative stress from acute renal IR injury may be alleviated by either Exendin-4 (i.e., Glucagon-like peptide-1 (GLP-1) analogue) or sitagliptin treatment through the induction of GLP-1 receptor (GLP-1R) expression
Exendin-9-39 inhibited the effect of sitagliptin on attenuating the acute kidney IR injury (Figure 1) To assess the effect of sitagliptin therapy on ameliorating acute kidney IR was inhibited by extendin-9-39, an antagonist of exendin-4, 24 hr acute kidney IR injury was done in additional six animals, i.e., IR only (n = 2), IR + sitagliptin (n = 2), and IR + sitagliptin + exendin-9-39
Summary
This study tested the hypothesis that exendin-4 and sitagliptin can effectively protect kidney from acute ischemia-reperfusion (IR) injury. Experimental studies have further revealed that inhibition of inflammatory reaction and suppression of the generations of pro-inflammatory cytokines and oxidative stress using immuno- or pharmaco-modulation significantly protect the kidney from acute IR injury [23,24,25,26,27]. Exendin-4 and liraglutide, two GLP-1 analogues, have been reported to have multiple cellular protective effects, including the protection of endothelial cells against senescence mainly through anti-oxidative [29,30,31] and anti-inflammatory [31,32,33] processes. Sitagliptin, currently used for treating type 2 diabetic patients, has been found to be able to enhance circulating GLP-1 levels through inhibition of DPP-IV activity [35,36] which, in turn, provides cardiovascular protective effect probably through the anti-inflammatory and anti-atherosclerotic actions of GLP-1 [37]. It is rational to hypothesize that the inflammatory reaction and oxidative stress from acute renal IR injury may be alleviated by either Exendin-4 (i.e., GLP-1 analogue) or sitagliptin treatment through the induction of GLP-1 receptor (GLP-1R) expression
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