Glucagon-like Peptide-1Receptor Agonist Exendin-4Ameliorates Transplant-induced Renal Ischemia-reperfusion Injury In The Rat

Part I glucagon-like peptide-1receptor agonist Exendin-4ameliorates renal ischemia-reperfusion injury in the ratBackground. Glucagon-like peptide-1receptor (GLP-1R) activation exert protective effects against reactive oxygen species by inducing the oxidative defense genes heme oxygenase-1(HO-1), and provides protection in mice transient focal cerebral ischemia and ischemia-reperfusion injury(IRI) in rat heart. GLP-1R also expressed in kidney. It is also unknown whether GLP-1R activation is still able to protect IRI in rat kidney.Methods. Using a SD rat model of renal IRI by40min of clamping of the left renal artery after right-sided nephrectomy. Before surgery, pretreatment with GLP-1R agonist: Exendin-4. Real-time polymerase chain reaction for the oxidative defense genes HO-1, western blot analysis for HO-1and GLP-1R. Renal function was assessed at baseline,24h and72h. After72h, kidneys were processed for histology and morphometric analysis, caspase-3and ED1immunohistochemistry. The degree of apoptosis of renal tubular cells was determined using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL).Results. Exendin-4pretreatment resulted in GLP-1R activation and up-regulation of HO-1. Preconditional activation of GLP-1R significantly improved serum creatinine levels in comparison to Veh (P<0.05). Furthermore, tissue injury, caspase-3and ED1expression, and apoptosis were less severe. Conclusion. These results demonstrate that preconditional activation of the GLP-1R in the kidney significantly protected against ischemia-reperfusion kidney injury in rats by increasing the HO-1expression. PartⅡ glucagon-like peptide-1receptor agonist Exendin-4ameliorates transplant-induced renal ischemia-reperfusion injury in the ratABSTRACTBackground. We have confirmed that preconditional activation of the GLP-1R with Exendin-4in the kidney significantly protected against ischemia-reperfusion kidney injury in rats by increasing the HO-1expression. We hypothesized that Exendin-4would protect transplant-induced renal ischemia-reperfusion injury in the rat.Methods. Using the Lewis rat kidney transplantation model, kidney graft preserved in Histidine-Tryptophane-Ketoglutarate(HTK) solution at4℃for18h, donor groups were given2μg/kg Exendin-4intraperitoneally prior2h to organ harvest, recipient groups were given2μg/kg Exendin-4intraperitoneally prior2h to reperfusion. Real-time polymerase chain reaction for the genes HO-1, TNF-a, IL-6, iNOS, Bax and BCL-2, Western blot analysis for HO-1and GLP-1R. Renal function was assessed at baseline,1d,3d,5d,7d. After24h, kidneys were processed for histology and morphometric analysis, caspase-3and ED1immunohistochemistry.Results. Exendin-4pretreatment resulted in GLP-1R activation in Lewis rat kidney transplantation model and up-regulation of HO-1, down-regulation of TNF-a、IL-6、iNOS、 Bax mRNA, tissue injury, caspase-3and ED1expression were less severe. Preconditional activation of GLP-IR significantly improved renal funtion and animal survival in recipients group (P<0.05).Conclusion. Preconditioning of both donors and recipients with Exendin-4significantly reduces transplant-induced renal ischemia-reperfusion injury in the rat and thus improves graft function. Some of our findings suggest that preconditioning recipients with Exendin-4has a greater impact on ischemia-reperfusion injury than application of Exendin-4to donors.