长效白细胞介素22治疗糖尿病肾病的作用及机制研究

Diabetic Nephropathy, characterized by progressive glomerulosclerosis and albuminuria, is a metabolic disease caused by diabetes with complicated pathogenesis and limited therapy. It has been elucidated by late-breaking studies that interconnected mechanisms of inflammasome and autophagy participate the onset and progression of diabetic nephropathy and could be novel targets for the treatment of diabetic nephropathy. Our preliminary study demonstrated that interleukin-22 expression was abnormally decreased in patients and mice with diabetic nephropathy, suggesting that deficiency of interleukin-22 may correlate with the progression of diabetic nephropathy. And we found that interleukin-22 gene therapy substantially alleviated renal pathological alterations, glycogen deposition and collagen accumulation in mice with established nephropathy. Meanwhile, interleukin-22 gene therapy could significantly attenuate renal fibrosis and restore renal function in diabetic nephropathy. Moreover, IL-22 gene therapy almost abolished activation of NLRP3 inflammasome in diabetic nephropathy. However, due to short half-life and rapid elimination of interleukin-22, it has to be administered frequently and chronically to attain better therapeutic effects for diabetic nephropathy. Thus, this project intends to utilize XTEN technology to construct long-acting interleukin-22 and aims at investigating the therapeutic effects of interleukin-22 on diabetic nephropathy and the underlying molecular mechanisms. On the basis of elucidating the role of inflammasome and autophagy in the therapeutic effects of interleukin-22, the project will explore in-depth the interacting relationship and molecular mechanisms between inflammasome and autophagy in the progression of diabetic nephropathy after interleukin-22 treatment, thus providing scientific basis for therapeutic strategies based on the regulation of inflammasome and autophagy for the treatment of diabetic nephropathy.

糖尿病肾病是由糖尿病引起的以肾小球硬化和蛋白尿为主要特征的代谢性疾病，病理机制复杂且缺乏有效治疗手段。炎性小体与细胞自噬密切相关共同参与糖尿病肾病发生和发展的关键环节，有望成为糖尿病肾病治疗的新靶点。课题组前期研究发现糖尿病肾病患者和小鼠白介素22的表达水平显著降低，提示白介素22缺乏与糖尿病肾病进展之间存在潜在联系；初步体内研究结果表明白介素22基因治疗显著缓解糖尿病肾病模型小鼠肾脏病理损伤、糖原沉积和胶原积聚，减轻肾纤维化并恢复肾功能；白介素22能逆转糖尿病肾病小鼠肾脏炎性小体的激活。但是由于白介素22体内半衰期短，糖尿病肾病作为慢性疾病治疗周期长，需频繁长期给药，因此本项目拟利用XTEN技术制备长效白介素22，研究其对糖尿病肾病的治疗作用及机制，揭示炎性小体和细胞自噬在白介素22治疗糖尿病肾病进程中的相互作用关系及分子机制，为基于调控炎性小体或细胞自噬设计糖尿病肾病治疗策略提供依据。

白细胞介素22（Interleukin-22, IL-22）具有维持机体代谢平衡和减轻肾脏炎症反应的重要作用，具有巨大的临床应用前景。本课题组前期研究结果表明白细胞介素22对糖尿病肾病具有一定的保护作用。但是，白细胞介素22在糖尿病肾病中的分子机制尚不明确。在接下来的研究中，我们首先确认了白细胞介素22显著逆转糖尿病肾病中肾脏NLRP3炎性小体的激活、Caspase-1的剪切以及白细胞介素1β的成熟，并在多种肾脏疾病模型中确认了IL-22对肾脏NLRP3炎性小体激活的调控作用。进一步机制研究表明，白细胞介素22可以通过激活AMPK/AKT信号通路激活PFKFB3产生肾脏细胞代谢重编程作用，从而抑制肾脏细胞的线粒体功能发挥对糖尿病肾病的肾脏保护作用。不仅如此，我们还构建了IL-22与抗VEGF-B单抗融合蛋白，该融合蛋白延长了IL-22在体内的半衰期，可以改善肾小球和肾小管脂质蓄积，同时减轻氧化应激和炎症反应，进一步改善糖尿病肾病。因此本课题的研究为临床应用IL-22治疗糖尿病肾病提供了新的思路和实验依据。