目的 探究利拉魯肽對(duì)糖尿病腎病大鼠的作用及其調(diào)控機(jī)制。方法 采取多次小劑量ip鏈脲佐菌素40 mg/kg構(gòu)建糖尿病腎病大鼠模型，分為模型組、利拉魯肽組、活性氧簇（ROS）抑制劑（NAC）組、利拉魯肽+NAC組，另設(shè)置對(duì)照組，每組10只。利拉魯肽組大鼠sc 200 μg/（kg·d）的利拉魯肽；NAC組大鼠ip 20 mg/（kg·d）的NAC；利拉魯肽+NAC組大鼠sc 200 μg/（kg·d）的利拉魯肽的同時(shí)ip 20 mg/（kg·d）的NAC；對(duì)照組和模型組大鼠sc等量的生理鹽水，1次/d，連續(xù)治療4周。全自動(dòng)分析儀檢測(cè)24 h尿微量蛋白排泄率（MAER）；血糖儀測(cè)定空腹血糖（FBG）；試劑盒檢測(cè)血清肌酐（Scr）、尿素氮（BUN）水平；HE染色、Masson染色觀察腎組織病理變化；二氫乙錠（DHE）熒光探針檢測(cè)腎組織活性氧（ROS）水平；化學(xué)比色法檢測(cè)腎組織丙二醛（MDA）含量、谷胱甘肽過(guò)氧化物酶（GSH）和超氧化物歧化酶（SOD）活性；Western blotting檢測(cè)腎組織NOD樣受體蛋白3（NLRP3）炎癥小體和焦亡相關(guān)蛋白表達(dá)。結(jié)果 與模型組相比，利拉魯肽組和NAC組大鼠MAER、Scr、BUN、FBG均顯著降低（P<0.05）；腎組織ROS、MDA含量顯著降低，GSH、SOD活性升高（P<0.05）；NLRP3炎癥小體相關(guān)蛋白[NLRP3、凋亡相關(guān)斑點(diǎn)樣蛋白（ASC）、Caspase-1]和焦亡相關(guān)蛋白[cleaved-Caspase-1、GSDMD-N、白細(xì)胞介素（IL）-1β、IL-18]表達(dá)均顯著降低（P<0.05、0.01）。與利拉魯肽組相比，利拉魯肽+NAC組上述指標(biāo)均得到進(jìn)一步改善，腎組織病理?yè)p傷進(jìn)一步減輕。結(jié)論 利拉魯肽能夠通過(guò)ROS-NLRP3炎癥小體途徑抑制腎組織氧化應(yīng)激介導(dǎo)的NLRP3炎癥小體活化，從而抑制細(xì)胞焦亡，并最終發(fā)揮抗糖尿病腎病腎損傷作用。

Objective To investigate the effect of liraglutide on diabetic nephropathy in rats and its regulatory mechanism. Methods The diabetic nephropathy rat model was constructed with multiple low-dose streptozocin 40 mg/kg, and was divided into model group, liraglutide group, ROS inhibitor (NAC) group, liraglutide + NAC group, and control group, with 10 rats in each group. Liraglutide group rats sc 200 μg/(kg·d) liraglutide, NAC group rats ip 20 mg/(kg·d) NAC, liraglutide + NAC group was sc 200 μg/(kg·d) of liraglutide and ip 20 mg/(kg·d) of NAC. Rats in control group and model group were treated with sc equal amount of normal saline once daily for 4 weeks. 24 h MAER was measured by automatic analyzer. FBG was measured by glucose meter. Scr and BUN levels were detected with the kit. The pathological changes of renal tissue were observed by HE staining and Masson staining. DHE fluorescent probe was used to detect ROS in renal tissue. The content of MDA and the activities of GSH and SOD were detected by chemical colorimetry. Expression of NLRP3 inflammasome and pyroptosis related protein were detected by Western blotting. Results Compared with model group, MAER, Scr, BUN and FBG in liraglutide group and NAC group were significantly decreased (P < 0.05). The contents of ROS and MDA in renal tissue were significantly decreased, while the activities of GSH and SOD were increased (P < 0.05). Expressions of NLRP3 inflammator-associated proteins (NLRP3, ASC, Caspase-1) and pyro related proteins (cleaved Caspase-1, GSDMD-N, IL-1β, IL-18) were significantly decreased (P < 0.05, 0.01). Compared with liraglutide group, the above indexes were further improved in liraglutide + NAC group, and the pathological injury of kidney tissue was further alleviated. Conclusion Liraglutide can inhibit the activation of NLRP3 inflammasome mediated by oxidative stress in renal tissue through ROS-NLRP3 inflammasome pathway, thereby inhibiting pyroptosis, and finally playing an anti diabetic nephropathy renal injury role.

R977