Glucagon-like peptide-1 (GLP-1) is a novel anti-diabetic agent used in clinical practice. Recently, it was reported to exert a renoprotective effect in the HK-2 cells and kidneys of diabetic rats, which was induced by one type of GLP-1 analogues liraglutide in the presence of high glucose. However, most of the previous findings mainly focused on its indirect effect in inhibiting the advanced glycation end products. Here, besides glycemic control, we also demonstrated a stimulatory role of liraglutide in promoting autophagy and relieving oxidative stress in Zucker diabetic fatty(ZDF) rats. The renoprotective effect of liraglutide has been demonstrated by significantly decreasing urinary albumin (P<0.01) and ameliorating renal pathological changes (P<0.001) in vivo. Besides that, proliferation of Hkc8 and HEK293 cells have been increased after treating with exendin-4, a GLP-1 receptor agonist. Moreover, the GLP-1 could positively improve the progression of autophagy in vivo and in vitro through regulating the autophagy-related protein LC3 and P62 via AMPK/mTOR signaling pathway. Simultaneously, it could reverse Nrf2 translocation into the nuclei, then suppress oxidative stress. In terms of mechanism, the renoprotective effect of the GLP-1 would be exerted via the GLP1R-AMPK-mTOR-autophagy-ROS signaling axis. The present study not only illustrates the renoprotective effect of the GLP-1 in DKD rats but also in the first time elucidates the underlying mechanism that is independent of controlling glucose, which implies that the GLP-1 might be a novel therapeutic strategy for the prevention and treatment of DKD.

中文翻译：

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GLP-1通过调节AMPK / mTOR途径自噬激活来减轻糖尿病肾病。

胰高血糖素样肽-1（GLP-1）是一种在临床实践中使用的新型抗糖尿病药。最近，据报道在高糖存在下由一种类型的GLP-1类似物利拉鲁肽诱导在糖尿病大鼠的HK-2细胞和肾脏中发挥肾脏保护作用。然而，大多数先前的发现主要集中在其抑制晚期糖基化终产物的间接作用上。在这里，除了血糖控制外，我们还证明了利拉鲁肽在促进Zucker糖尿病性脂肪（ZDF）大鼠中自噬和缓解氧化应激中的刺激作用。利拉鲁肽的肾保护作用已通过在体内显着降低尿白蛋白（P <0.01）和改善肾脏病理变化（P <0.001）证明。除此之外，用GLP-1受体激动剂exendin-4处理后，Hkc8和HEK293细胞的增殖增加。此外，GLP-1可以通过AMPK / mTOR信号通路调节自噬相关蛋白LC3和P62，从而积极改善体内和体外自噬的进程。同时，它可以逆转Nrf2易位到核中，然后抑制氧化应激。就机理而言，GLP-1的肾保护作用将通过GLP1R-AMPK-mTOR-自噬-ROS信号转导轴发挥。本研究不仅说明了GLP-1在DKD大鼠中的肾脏保护作用，而且首次阐明了独立于控制葡萄糖的潜在机制，这表明GLP-1可能是预防该疾病的一种新的治疗策略。和DKD的治疗。