Glucagon-like peptide-1 alleviates diabetic kidney disease through activation of autophagy by regulating AMP-activated protein kinase-mammalian target of rapamycin pathway
| Autor: | Li Yang, Shuang-Li Yang, Wen Xu, Xiaoyun Zhuo, Yanzhen Cheng, Ji-Yu Wang, Shitao Rao, Chuman Lin |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_specialty
Physiology Endocrinology Diabetes and Metabolism Disease AMP-Activated Protein Kinases Glucagon-Like Peptide-1 Receptor Diabetes Mellitus Experimental AMP-activated protein kinase Glucagon-Like Peptide 1 Physiology (medical) Internal medicine Autophagy Animals Humans Medicine Diabetic Nephropathies Cells Cultured Diabetic kidney biology business.industry TOR Serine-Threonine Kinases Glucagon-like peptide-1 Rats Rats Zucker Clinical Practice HEK293 Cells Endocrinology biology.protein Exenatide business Signal Transduction |
| Zdroj: | American Journal of Physiology-Endocrinology and Metabolism. 319:E1019-E1030 |
| ISSN: | 1522-1555 0193-1849 |
| DOI: | 10.1152/ajpendo.00195.2019 |
| Popis: | Glucagon-like peptide-1 (GLP-1) is a novel antidiabetic agent used in clinical practice. Recently, it was reported to exert a renoprotective effect in the human kidney-2 cells and kidneys of diabetic rats, which was induced by one type of GLP-1 analog, 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 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 human epithelial kidney cell line HKC-8 and human embryonic kidney-293 cells has increased after treating with exendin-4, a GLP-1 receptor (GLP-1R) agonist. Moreover, GLP-1 could positively improve the progression of autophagy in vivo and in vitro through regulating the autophagy-related protein light chain 3 and p62 via AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling pathway. Simultaneously, it could reverse NF-erythroid 2-related factor 2 (NRF2) translocation into the nuclei and suppress oxidative stress. In terms of mechanism, the renoprotective effect of GLP-1 would be exerted via the GLP-1R-AMPK-mTOR-autophagy-reactive oxygen species signaling axis. The present study not only illustrates the renoprotective effect of GLP-1 in diabetic kidney disease (DKD) rats, but also for the first time elucidates the underlying mechanism that is independent of controlling glucose, which implies that GLP-1 might be a novel therapeutic strategy for the prevention and treatment of DKD. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|