Targeting AMPK in Diabetes and Diabetic Complications: Energy Homeostasis, Autophagy and Mitochondrial Health

Madhavi, Y.V.; Gaikwad, Nikhil Baliram; Yerra, Veera Ganesh; Kalvala, Anil Kumar; Nanduri, Srinivas; Kumar, Ashutosh

doi:10.2174/0929867325666180406120051

Cited by 80 publications

(52 citation statements)

References 105 publications

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“…AMPK plays a major role in cellular energy metabolism and redox homeostasis. Previous evidence suggested that AMPK activation can decrease reactive oxygen species (ROS) production and protect mitochondria biogenesis as well 21. A significant reduction in the p-AMPK / AMPK protein ratio was detected in diabetic mice compared with that in controls by immunoblotting (Fig.…”

Section: Resultsmentioning

confidence: 82%

“…Reductions of the mitochondrial membrane potential in podocytes cultured in HG was alleviated after Sirt6 plasmid transfection. AMPK is a highly conserved cellular bioenergetic sensor that contributes to the regulation of multiple cellular functions ranging from energy homeostasis to cell death regulation21. Growing evidence has suggested that AMPK signaling malfunction is proved to have pathological implications in mitochondrial diseases.…”

Section: Discussionmentioning

confidence: 99%

“…As a key enzymatic protein, AMPK links energy sensing to metabolic manipulation. In addition, AMPK exerts mitochondrial protection by regulating the biogenesis and degradation of mitochondria 21-26. Administration of an AMPK agonist to streptozotocin (STZ)-induced diabetic mice protected the animals from renal damage via improving mitochondrial function 27.…”

Section: Introductionmentioning

confidence: 99%

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Sirt6 Suppresses High Glucose-Induced Mitochondrial Dysfunction and Apoptosis in Podocytes through AMPK Activation

et al. 2019

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Previous studies have shown that mitochondrial dysfunction plays an important role in high- glucose(HG)-induced podocyte injury and thus contributes to the progression of diabetic nephropathy(DN). The histone deacetylase Sirtuin6 (Sirt6) has been revealed to have an essential role in the regulation of mitochondrial function in skeletal muscle and cardiomyocytes. However, its specific role in mitochondrial homeostasis in podocytes is undetermined. Here, we aimeds to explore the physiological function of Sirt6 in podocyte mitochondria and apoptosis under HG conditions and explore the possible mechanism. Herein, we observed that Sirt6-WT-1 colocalization was suppressed in the glomeruli of patients with DN. In addition, diabetic mice exhibited reduced Sirt6 expression and AMP kinase (AMPK) dephosphorylation accompanied by mitochondrial morphological abnormalities. In vitro, podocytes exposed to HG presented with mitochondrial morphological alterations and podocyte apoptosis accompanied by Sirt6 and p-AMPK downregulation. In addition, HG promoted a decrease in mitochondrial number and an increase in mitochondrial superoxide production as well as a decreased mitochondrial membrane potential. ROS production was also increased in HG-treated podocytes. Conversely, all these mitochondrial defects induced by HG were significantly alleviated by Sirt6 plasmid transfection. Sirt6 overexpression simultaneously alleviated HG-induced podocyte apoptosis and oxidative stress, as well as increased AMPK phosphorylation. Increased levels of H3K9ac and H3K56ac induced by HG were attenuated in podocytes transfected with Sirt6 plasmids. Therefore, these results elucidated that Sirt6 protects mitochondria of podocytes and exerts anti-apoptotic effects via activating AMPK pathway. The present findings provide key insights into the pivotal role of mitochondria regulation by SIRT6 in its protective effects on podocytes.

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Section: Resultsmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sirt6 Suppresses High Glucose-Induced Mitochondrial Dysfunction and Apoptosis in Podocytes through AMPK Activation

et al. 2019

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“…AMPK is highly expressed in renal cells, such as podocytes, and plays a crucial role in maintaining glucose homeostasis (20). Previous studies have proposed a protective role for AMPK signaling in mitochondrial function (17,21,22). Notably, a decrease in the p-AMPK/AMPK protein ratio was witnessed in the diabetic rats, which prompted the investigation into the underlying role of sesn2 in AMPK regulation (Fig.…”

Section: Histopathological Features Of Glomeruli and Podocyte Injury mentioning

confidence: 99%

Sestrin‑2 regulates podocyte mitochondrial dysfunction�and apoptosis under high‑glucose conditions via AMPK

Lin

Chen

et al. 2020

Int J Mol Med

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diabetic kidney disease (dKd) is a severe form of microangiopathy among diabetic patients, of which podocyte injury is one of the more predominant features. There is increasing evidence to suggest that mitochondrial dysfunction is associated with podocyte injury, thus contributing to the progression of DKD. Initially identified as a p53 target protein, the endogenous antioxidant protein, sestrin-2 (sesn2), has recently attracted attention due to its potential function in various inflammatory diseases. However, the association between sesn2 and podocytes in dKd remains unclear. In the present study, to elucidate the role of sesn2 in podocyte mitochondrial dysfunction, the effects of sesn2 on the regulation of AMP-activated protein kinase (AMPK) were examined in vitro and in vivo. Abnormal mitochondria were found in rats with streptozotocin-induced diabetes, and hyperglycemia downregulated the expression of sesn2. The upregulation of sesn2 increased the level of AMPK phosphorylation, and thus ameliorated mitochondrial dysfunction under high glucose conditions (HG). On the whole, these results suggest that sesn2 is associated with mitochondrial dysfunction in podocytes under HG conditions. In addition, the decreased expression of sesn2 may be a therapeutic target for dKd.

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“…Notably, LPSinduced acute myocardial injury can be significantly attenuated by upregulation of autophagy (17,18). The activation of AMP-activated protein kinase (AMPK) signaling is effective in upregulating autophagy (19,20). It might be a promising way to alleviate LPS-induced acute myocardial injury via the activation of AMPK signaling, upregulation of autophagy, and suppression of inflammation.…”

Section: Introductionmentioning

confidence: 99%

The Protective Effects of Melatonin Against LPS-Induced Septic Myocardial Injury: A Potential Role of AMPK-Mediated Autophagy

Zheng

et al. 2020

Front. Endocrinol.

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Aim: Melatonin is an indolamine secreted by the pineal gland, as well as most of the organs and tissues. In addition to regulating circadian biology, studies have confirmed the multiple pharmacological effects of melatonin. Melatonin provides a strong defense against septic myocardial injury. However, the underlying mechanism has not been fully described. In this study, we investigated the protective effects of melatonin against lipopolysaccharide (LPS)-induced myocardial injury as well as the mechanisms involved.Methods: Mice were intraperitoneally injected with LPS to induce a septic myocardial injury model or an LPS shock model, depending on the dose of LPS. Melatonin was given (20 mg/kg/day, via intraperitoneal injection) for a week prior to LPS insult. 6 h after LPS injection, echocardiographic analysis, TUNEL staining, transmission electron microscopy (TEM), western blot, quantitative real-time PCR and ELISA were used to investigate the protective effects of melatonin against LPS induced myocardial injury. AMPK inhibitor, autophagy activator and inhibitor, siRNAs were used for further validation.Results: Survival test showed that melatonin significantly increased the survival rate after LPS-induced shock. In the sepsis model, melatonin markedly ameliorated myocardial dysfunction, decreased the release of inflammatory cytokines, activated AMP-activated protein kinase (AMPK), improved mitochondrial function, and activated autophagy. To confirm whether the protection of melatonin was mediated by AMPK and autophagy, Compound C, an AMPK inhibitor; 3-MA, an autophagy inhibitor; and Rapamycin (Rapa), an autophagy activator, were used in this study. AMPK inhibition down-regulated autophagy, abolished protection of melatonin, as indicated by significantly decreased cardiac function, increased inflammation and damaged mitochondrial function. Furthermore, autophagy inhibition by 3-MA significantly impaired the protective effects of melatonin, whereas autophagy activation by Rapa reversed LPS + Compound C induced myocardial injury. In addition, in vitro studies further confirmed the protection of melatonin against LPS-induced myocardial injury and the mechanisms involving AMPK-mediated autophagy signaling.Di et al. Melatonin Reduces Septic Myocardial InjuryConclusions: In summary, our results demonstrated that melatonin protects against LPS-induced septic myocardial injury by activating AMPK mediated autophagy pathway.

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Targeting AMPK in Diabetes and Diabetic Complications: Energy Homeostasis, Autophagy and Mitochondrial Health

Cited by 80 publications

References 105 publications

Sirt6 Suppresses High Glucose-Induced Mitochondrial Dysfunction and Apoptosis in Podocytes through AMPK Activation

Sirt6 Suppresses High Glucose-Induced Mitochondrial Dysfunction and Apoptosis in Podocytes through AMPK Activation

Sestrin‑2 regulates podocyte mitochondrial dysfunction�and apoptosis under high‑glucose conditions via AMPK

The Protective Effects of Melatonin Against LPS-Induced Septic Myocardial Injury: A Potential Role of AMPK-Mediated Autophagy

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