The protective effects of rapamycin on cell autophagy in the renal tissues of rats with diabetic nephropathy via mTOR-S6K1-LC3II signaling pathway

Liu, Lei; Yang, Lijuan; Chang, Baochao; Zhang, Jiqiang; Guo, Yaling; Yang, Xiaoling

doi:10.1080/0886022x.2018.1489287

Cited by 32 publications

(25 citation statements)

References 18 publications

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“…Hypoxia is one of the causes of renal tubular injury in the elderly. With the increase of age, hypoxia weakens autophagy, which leads to the accumulation of ROS in damaged mitochondria and mitochondria in kidneys . In diabetic mice, rapamycin can inhibit mTOR and up‐regulate autophagy, inhibit podocyte apoptosis and protect renal function .…”

Section: Discussionmentioning

confidence: 99%

Metformin alleviates renal injury in diabetic rats by inducing Sirt1/FoxO1 autophagic signal axis

Liu

et al. 2020

Clin Exp Pharma Physio

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Diabetic nephropathy (DN) is the major microvascular complication of diabetes mellitus and the most important cause of end‐stage renal disease worldwide. Metformin is the preferred oral hypoglycaemic drug for type 2 diabetes mellitus (T2DM). Recent studies have shown that besides lowering blood glucose, metformin also has protective effects on renal function, but its mechanism is not clear. In this study, we established a diabetic rat model by high‐fat feeding combined with intraperitoneal injection of streptozotocin. Their changes of renal function, oxidative stress, histopathology and structure, and autophagy were observed after 8 weeks of metformin treatment at different dose. Sirt1 inhibitor EX527 and metformin were used to observe whether the protective effect of metformin on DN kidney was achieved through the Sirt1/FoxO1 autophagic signalling pathway. The results showed that metformin could protect renal function by up‐regulating autophagy level, alleviating oxidative stress level of renal tissue and pathological and structural changes of glomeruli, and inhibiting the expression of extracellular matrix. Sirt1 inhibitor could block the protective effect of metformin on kidney of diabetic rats, suggesting that metformin could alleviate kidney injury in diabetic rats by inducing Sirt1/FoxO1 autophagy signal axis. So metformin could alleviate renal injury in diabetic rats, which may be achieved by regulating Sirt1/FoxO1 autophagic signalling pathway and inducing renal autophagy.

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Section: Discussionmentioning

confidence: 99%

Metformin alleviates renal injury in diabetic rats by inducing Sirt1/FoxO1 autophagic signal axis

Liu

et al. 2020

Clin Exp Pharma Physio

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“…Formation of LC3Ⅱ from LC3Ⅰ is a critical step in autophagosome constitution [43,44] and BCL-1 is regarded as an indicator of autophagy activity [9]. Our studies showed that FGF21 upregulated the mRNA and…”

Section: Discussionmentioning

confidence: 58%

The therapeutic effects of FGF21 on diabetic nephropathy are realized by augmenting autophagy via AMPK/mTOR signaling pathway

Meng¹,

Cao²,

Khoso³

et al. 2020

Preprint

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Accumulating evidence demonstrates that FGF21 plays a preventive role in the development of diabetic nephropathy (DN). However, little is known about the therapeutical effects of FGF21 on DN and underlying mechanism. In this study, FGF21 significantly ameliorated blood glucose, HbAlc, insulin resistance, renal function and histopathological change in DN mice (BKS-Leprem2Cd479/Gpt), which develop abnormalities in renal morphology and function. Our results showed that administration of FGF21 upregulated the autophagy related genes LC3Ⅱ and BCL-1 mRNA and protein expression levels. D-glucose was used for high glucose (HG) model in mesangial cells. The results showed that treatment with FGF21 reduced the levels of ROS, AGEs and inflammatory cytokines and significantly downregulated the protein expression of PCNA. Meanwhile, FGF21 significantly enhanced the expression of LC3Ⅱ and BCL-1. Besides, Our studies showed that administration of FGF21 significantly upregulated the phosphorylation of AMPK and downregulated phosphorylation of mTOR. Meanwhile, the effects of FGF21 on autophagy were reversed by siRNA against β-klotho. In conclusion, The therapeutic effects of FGF21 on diabetic nephropathy are realized and FGF21 ameliorates mesangial cell glucotoxicity and abnormal proliferation in vitro by augmenting autophagy via AMPK/mTOR pathway. These results suggest that FGF21 can be a therapeutic target against DN.

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“…The AMPK-mTOR axis is known to regulate autophagy; maintaining the cellular homeostasis via AMPK is considered to activate autophagy, whereas autophagy is inhibited by mTOR ( 27 ). The present study investigated whether metformin influenced autophagy via the AMPK-mTOR axis in diabetic mice.…”

Section: Resultsmentioning

confidence: 99%

Metformin attenuates diabetic renal injury via the AMPK‑autophagy axis

et al. 2021

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Diabetic nephropathy (DN) is a clinical condition characterized by kidney damage that is observed in patients with diabetes. DN is the main cause of end-stage renal disease (ESRD), which is the final stage of chronic kidney disease. Increasing evidence suggests that metformin, a characteristic oral hypoglycemic drug used for treating diabetes, exerts beneficial effects on various medical conditions and diseases, including cancer, cardiovascular diseases and thyroid-related disorders. However, the impact of metformin on DN remains unknown. The present study investigated whether metformin could attenuate the inflammatory response, fibrosis and increased oxidative stress observed during DN in diabetic/dyslipidemic (db/db) mice. The kidneys of the mice (12-16 weeks) were isolated for immunohistochemistry and western blotting. The results demonstrated that metformin significantly reduced the oxidative damage and fibrosis in the kidneys of db/db mice. Furthermore, metformin treatment significantly inhibited the generation of inflammatory cytokines, including TNF-α and IL-1β in db/db mice. These effects were induced by the activation of the AMP-activated protein kinase (AMPK) pathway, which was mediated by increased phosphorylation of AMPK and mammalian target of rapamycin (mTOR), resulting in autophagy and the simultaneous decrease in reactive oxygen species production, cell apoptosis and inflammatory response. These findings suggested that metformin may reduce DN damage via regulation of the AMPK-mTOR-autophagy axis and indicated that metformin may be considered as a potential target in the treatment of DN.

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The protective effects of rapamycin on cell autophagy in the renal tissues of rats with diabetic nephropathy via mTOR-S6K1-LC3II signaling pathway

Cited by 32 publications

References 18 publications

Metformin alleviates renal injury in diabetic rats by inducing Sirt1/FoxO1 autophagic signal axis

Metformin alleviates renal injury in diabetic rats by inducing Sirt1/FoxO1 autophagic signal axis

The therapeutic effects of FGF21 on diabetic nephropathy are realized by augmenting autophagy via AMPK/mTOR signaling pathway

Metformin attenuates diabetic renal injury via the AMPK‑autophagy axis

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