胰高血糖素样肽-1 受体激动剂 Exendin-4 减轻大鼠心脏死亡来源供肾肾脏移植缺血-再灌注损伤的研究

Glucagon-like peptide-1 (GLP-1) is a polypeptide hormone that is secreted from the L cell of the intestine. GLP-1 can induce pancreatic b-cell proliferation, powerfully inhibit glucagon secretion, and control blood glucose levels [8]. Exendin-4 is a GLP-1 receptor (GLP-1R) agonist, it shares functions with GLP-1, and was approved for the treatment of type 2 diabetes mellitus. Exendin-4 can inhibit b-cell apoptosis, decrease expression of the apoptotic factor caspase-3, and prevent reactive oxygen species by inducing the oxidative defense gene HO-1. Apart from their function in diabetes, it has been proposed that GLP-1 and EX-4 have protective effects against ischemia-reperfusion injury on the heart. We have confirmed that preconditional activation of the GLP-1R with Exendin-4 in the kidney significantly protected against ischemia-reperfusion kidney injury in rats by increasing the HO-1 expression. We hypothesized that Exendin-4 would protect transplant-induced renal ischemia-reperfusion injury in the in the kidney grafts donated after cardiac death.Using the Lewis rat kidney transplantation model, donor groups and recipient groups were given Exendin-4.Renal function was assessed at baseline, 1,3,5,7,14,21,28d. After 24 h, kidneys were processed for histology and morphometric analysis, caspase-3 and ED1 immunohistochemistry, protein and gene of oxidation and nflammation will be assessed.This research will demonstrate the mechanisms responsible for transplant-induced renal ischemia-reperfusion injury in the kidney grafts donated after cardiac death.

胰高血糖素-1（GLP-1）能诱导胰腺 β 细胞增殖，强烈抑制胰高血糖素释放，从而控制血糖水平。Exendin-4是GLP-1 受体激活剂，与 GLP-1 具有相似的降糖功能，已经被批准用于临床治疗2型糖尿病。研究发现 GLP-1 和 Exendin-4能减轻大鼠心脏的缺血-再灌注损伤，GLP-1 受体广泛表达于机体多种组织和器官，肾脏也有广泛的表达。我们证实Exendin-4激活大鼠肾脏GLP-1R，诱导肾脏HO-1基因和蛋白上调，减轻大鼠肾脏的热缺血-再灌注损伤；本研究探讨Exendin-4是否能减轻大鼠心脏死亡供体来源肾脏肾移植术后移植肾脏缺血-再灌注损伤。采用Lewis大鼠同系肾移植模型，供体和受体分别使用：Exendin-4。术后通过对植肾移植肾脏病理学，一个月内受体生存率和肾功能；氧化和炎症基因与蛋白表达；阐明 Exendin-4减轻移植肾脏冷热缺血--再灌注损伤的机制。

Exendin-4 是胰高血糖素-1（GLP-1）受体激活剂，能抑制胰高血糖素释放，从而降低血糖。人工合成Exendin-4类似物艾塞那肽（Exenatide）用于临床治疗2 型糖尿病。动物实验研究发现 Exendin-4 能减轻大鼠心脏热缺血-再灌注损伤。我们前期研究发现预先以Exendin-4 激活大鼠肾脏GLP-1R，能减轻大鼠肾脏的热缺血-再灌注损伤。我们推测预先激活肾脏GLP-1R能减轻心脏死亡供体来源供肾移植缺血-再灌注损伤。在此背景上，我们通过构建同系大鼠心脏死亡供体来源肾脏肾移植模型，发现了心脏死亡供体来源肾脏经历热缺血和冷缺血过程，PARP，VDAC1，cleaved caspase-3蛋白表达上调，caspase-3途径诱导的细胞凋亡是影响供肾质量的重要因素，预先激活肾脏GLP-1R能显著抑制热缺血和冷缺血诱导的供肾肾小管细胞凋亡，减轻再灌注后TNF-α, IL-6, IL-1β等炎症因子的表达和ED1阳性细胞的浸润，从而减轻移植肾缺血-再灌注损伤，改善移植肾功能，提高术后生存率。而且我们将研究扩展，通过构建大鼠脑死亡供肾移植模型，证实激活供肾GLP-1R能显著减轻脑死亡供肾损伤。