Empagliflozin Enhances Autophagy, Mitochondrial Biogenesis, and Antioxidant Defense and Ameliorates Renal Ischemia/Reperfusion in Nondiabetic Rats

Ala, Moein; Khoshdel, Mohammad Reza Fallahpour; Dehpour, Ahmad Reza

doi:10.1155/2022/1197061

Cited by 40 publications

(37 citation statements)

References 36 publications

(41 reference statements)

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“…Similarly, as in heart and lung, phosphorylation of AMPK and ERK1/2 was improved[ 96 ]. Remarkably, similar observations were made in non-diabetic rats[ 97 ].…”

Section: Experimental Modelssupporting

confidence: 85%

A review of potential mechanisms and uses of SGLT2 inhibitors in ischemia-reperfusion phenomena

Quentin¹,

Singh²,

Nguyen³

2022

WJD

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Recently added to the therapeutic arsenal against chronic heart failure as a first intention drug, the antidiabetic drug-class sodium-glucose cotransporter-2 inhibitors (SGLT2i) showed efficacy in decreasing overall mortality, hospitalization, and sudden death in patients of this very population, in whom chronic or acute ischemia count among the first cause. Remarkably, this benefit was observed independently from diabetic status, and benefited both preserved and altered ventricular ejection fraction. This feature, observed in several large randomized controlled trials, suggests additional effects from SGLT2i beyond isolated glycemia control. Indeed, both in-vitro and animal models suggest that inhibiting the Na + /H + exchanger (NHE) may be key to preventing ischemia/ reperfusion injuries, and by extension may hold a similar role in ischemic damage control and ischemic preconditioning. Yet, several other mechanisms may be explored which may help better target those who may benefit most from SGLT2i molecules. Because of a large therapeutic margin with few adverse events, ease of prescription and potential pharmacological efficacity, SGLT2i could be candidate for wider indications. In this review, we aim to summarize all evidence which link SGLT2i and ischemia/reperfusion injuries modulation, by first listing known mechanisms, including metabolic switch, prevention of lethal arrythmias and others, which portend the latter, and second, hypothesize how the former may interact with these mechanisms.

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“…Similarly, as in heart and lung, phosphorylation of AMPK and ERK1/2 was improved[ 96 ]. Remarkably, similar observations were made in non-diabetic rats[ 97 ].…”

Section: Experimental Modelssupporting

confidence: 85%

A review of potential mechanisms and uses of SGLT2 inhibitors in ischemia-reperfusion phenomena

Quentin¹,

Singh²,

Nguyen³

2022

WJD

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“…Although the first interest in SGLT2i was their glucose-lowering capacity, lately there have been described pleiotropic effects of SGLT2i in a wide range of targets throughout the body ( Figure 2 ). Using different experimental approaches and in different scenarios, SGLT2i have been shown to participate in the regulation of osmotic natriuresis and diuresis [ 103 , 104 ], hypertension [ 105 ], glucagon [ 106 , 107 ] and energy metabolism [ 108 , 109 , 110 , 111 , 112 ], mitochondrial function and biogenesis [ 113 , 114 , 115 , 116 , 117 , 118 ], autophagy [ 112 , 119 , 120 , 121 , 122 , 123 , 124 , 125 ], oxidative stress [ 46 , 123 , 126 , 127 , 128 , 129 ], fibrosis [ 46 , 130 , 131 , 132 , 133 ], apoptosis [ 122 , 128 , 134 , 135 , 136 , 137 , 138 , 139 ], endoplasmic reticulum stress [ 124 , 139 , 140 , 141 , 142 , 143 ], or inflammation [ 120 ,…”

Section: Sglt2 Inhibitorsmentioning

confidence: 99%

Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Regulation of Inflammatory Processes in Animal Models

Feijóo‐Bandín

Aragón-Herrera

Otero-Santiago

et al. 2022

IJMS

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Sodium-glucose co-transporter 2 inhibitors, also known as gliflozins, were developed as a novel class of anti-diabetic agents that promote glycosuria through the prevention of glucose reabsorption in the proximal tubule by sodium-glucose co-transporter 2. Beyond the regulation of glucose homeostasis, they resulted as being effective in different clinical trials in patients with heart failure, showing a strong cardio-renal protective effect in diabetic, but also in non-diabetic patients, which highlights the possible existence of other mechanisms through which gliflozins could be exerting their action. So far, different gliflozins have been approved for their therapeutic use in T2DM, heart failure, and diabetic kidney disease in different countries, all of them being diseases that have in common a deregulation of the inflammatory process associated with the pathology, which perpetuates and worsens the disease. This inflammatory deregulation has been observed in many other diseases, which led the scientific community to have a growing interest in the understanding of the biological processes that lead to or control inflammation deregulation in order to be able to identify potential therapeutic targets that could revert this situation and contribute to the amelioration of the disease. In this line, recent studies showed that gliflozins also act as an anti-inflammatory drug, and have been proposed as a useful strategy to treat other diseases linked to inflammation in addition to cardio-renal diseases, such as diabetes, obesity, atherosclerosis, or non-alcoholic fatty liver disease. In this work, we will review recent studies regarding the role of the main sodium-glucose co-transporter 2 inhibitors in the control of inflammation.

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“…Furthermore, dapagliflozin alleviates pressure overload-induced myocardial remodeling in mice via inhibiting ER stress-mediated apoptosis ( 65 ). Empagliflozin improved renal ischemia/reperfusion injury in non-diabetic rats by promoting mitochondrial biogenesis and inhibiting oxidative stress and apoptosis ( 66 ). In the murine model of left ventricular pressure overload, empagliflozin aids the suppression of endothelial apoptosis, the maintenance of capillarization, and the improvement of cardiac systolic dysfunction ( 67 ).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Cardiorenal Protection With SGLT2 Inhibitors in Patients With T2DM Based on Network Pharmacology

Wang

Li²,

Sun³

et al. 2022

Front. Cardiovasc. Med.

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PurposeSodium-glucose cotransporter 2 (SGLT2) inhibitors have cardiorenal protective effects regardless of whether they are combined with type 2 diabetes mellitus, but their specific pharmacological mechanisms remain undetermined.Materials and MethodsWe used databases to obtain information on the disease targets of “Chronic Kidney Disease,” “Heart Failure,” and “Type 2 Diabetes Mellitus” as well as the targets of SGLT2 inhibitors. After screening the common targets, we used Cytoscape 3.8.2 software to construct SGLT2 inhibitors' regulatory network and protein-protein interaction network. The clusterProfiler R package was used to perform gene ontology functional analysis and Kyoto encyclopedia of genes and genomes pathway enrichment analyses on the target genes. Molecular docking was utilized to verify the relationship between SGLT2 inhibitors and core targets.ResultsSeven different SGLT2 inhibitors were found to have cardiorenal protective effects on 146 targets. The main mechanisms of action may be associated with lipid and atherosclerosis, MAPK signaling pathway, Rap1 signaling pathway, endocrine resistance, fluid shear stress, atherosclerosis, TNF signaling pathway, relaxin signaling pathway, neurotrophin signaling pathway, and AGEs-RAGE signaling pathway in diabetic complications were related. Docking of SGLT2 inhibitors with key targets such as GAPDH, MAPK3, MMP9, MAPK1, and NRAS revealed that these compounds bind to proteins spontaneously.ConclusionBased on pharmacological networks, this study elucidates the potential mechanisms of action of SGLT2 inhibitors from a systemic and holistic perspective. These key targets and pathways will provide new ideas for future studies on the pharmacological mechanisms of cardiorenal protection by SGLT2 inhibitors.

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Empagliflozin Enhances Autophagy, Mitochondrial Biogenesis, and Antioxidant Defense and Ameliorates Renal Ischemia/Reperfusion in Nondiabetic Rats

Cited by 40 publications

References 36 publications

A review of potential mechanisms and uses of SGLT2 inhibitors in ischemia-reperfusion phenomena

A review of potential mechanisms and uses of SGLT2 inhibitors in ischemia-reperfusion phenomena

Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Regulation of Inflammatory Processes in Animal Models

Mechanisms of Cardiorenal Protection With SGLT2 Inhibitors in Patients With T2DM Based on Network Pharmacology

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