Empagliflozin reduces the senescence of cardiac stromal cells and improves cardiac function in a murine model of diabetes

Madonna, Rosalinda; Doria, Vanessa; Minnucci, Ilaria; Pucci, Angela; Pierdomenico, Donato Sante; Caterina, Raffaele De

doi:10.1111/jcmm.15699

Cited by 28 publications

(12 citation statements)

References 46 publications

(74 reference statements)

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“…Additionally, empagliflozin improves cardiac function in individuals with diabetes, with improvement in most of the organs under empagliflozin intervention. [20][21][22][23] Therefore, in this study, we investigated the effect of empagliflozin among SGLT2is on lipid metabolism in DN. When excessive energy accumulates in the body, the conversion barrier exceeds the capacity to store subcutaneous white adipose tissue, and heterotopic lipid deposition occurs in the liver, kidney and skeletal muscle.…”

Section: Discussionmentioning

confidence: 99%

Empagliflozin Regulates the AdipoR1/p-AMPK/p-ACC Pathway to Alleviate Lipid Deposition in Diabetic Nephropathy

Zhang¹,

Ni²,

Zha³

et al. 2021

DMSO

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Background: Abnormal lipid deposition in the progress of diabetic nephropathy (DN) plays an important role in a number of studies that have shown that SGLT2 inhibitor (SGLT2i) empagliflozin plays an important role in lipid metabolism, but its mechanism is still unclear. Methods: We aimed to explore the effect of empagliflozin on lipid levels in kidney cancer patients with DN and postoperative patients without DN kidney carcinoma; the patients with DN showed ectopic lipid deposition. In type 2 diabetes model mice induced by streptozotocin (STZ) and a high-fat diet, combined AMPK plus empagliflozin or empagliflozin inhibitor plus compound C was applied, followed by analyses of the blood, urine and kidney indexes to observe the correlation between SGLT2i and AMPK and lipid metabolism in diabetic kidney disease. We determined whether DN in patients with renal tubular atrophy involved lipid metabolism. Results: In clinical specimens, the adiponectin receptor AdipoR1 was reduced, and the phosphorylation acetyl-CoA carboxylase (p-ACC) was increased. In vitro and in vivo pathological immunofluorescence and Western blotting confirmed that, under the condition of high glucose, malpighian tubules displayed ectopic lipid deposition and expressed related lipid parameters accompanied by fibrosis. Empagliflozin intervention reduced lipid deposition fibrosis and renal tubular atrophy, and the addition of compound C promoted disease progression. Moreover, siAdipoR1 transfection proved that AdipoR1 affected P-AMPK and then p-ACC affected lipid metabolism in renal tubular cells. Conclusion: According to the above experimental results, empagliflozin could reduce lipid metabolism of DN through AdipoR1/P-AMPK/P-ACC pathway and delay DN progress.

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Section: Discussionmentioning

confidence: 99%

Empagliflozin Regulates the AdipoR1/p-AMPK/p-ACC Pathway to Alleviate Lipid Deposition in Diabetic Nephropathy

Zhang¹,

Ni²,

Zha³

et al. 2021

DMSO

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“…Empagliflozin reduces high glucose-induced RECK suppression, oxidative stress and epithelial-to-mesenchymal transition in cultured kidney proximal tubule cells and these beneficial effects are partially associated with p38 ( 116 ). Empagliflozin also attenuates the aging of cardiac stromal cells and improves heart function in a diabetic mouse model by targeting P38 ( 117 ). Canagliflozin protects endothelium function in APOE -deficient mice via inhibiting P38 activation ( 118 ).…”

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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“…By blocking sodium glucose co-transport and reducing blood glucose levels, SGLT2i demonstrate improved renal and cardiovascular outcomes in patients with T2DM and diabetic nephropathy [ 92 , 93 , 94 ]. Whilst initial protection is thought to stem from a decrease in glomerular hyperfiltration, several studies demonstrate that SGLT2i confer protection via suppression of inflammation and fibrosis, albeit the widespread mechanisms remain to be fully elucidated [ 95 , 96 , 97 ]. However, with prescription targeted to individuals with T2DM as opposed to T1DM and potential side effects that include ketoacidosis [ 98 ], increased risk of amputation [ 99 ], and increased genitourinary tract infection [ 100 ], SGLT2i are not a one size fits all.…”

Section: Targeting Inflammation In Microvascular Complications Of Diabetesmentioning

confidence: 99%

Connexin 43: A Target for the Treatment of Inflammation in Secondary Complications of the Kidney and Eye in Diabetes

Cliff

Williams

Chadjichristos

et al. 2022

IJMS

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Of increasing prevalence, diabetes is characterised by elevated blood glucose and chronic inflammation that precedes the onset of multiple secondary complications, including those of the kidney and the eye. As the leading cause of end stage renal disease and blindness in the working population, more than ever is there a demand to develop clinical interventions which can both delay and prevent disease progression. Connexins are membrane bound proteins that can form pores (hemichannels) in the cell membrane. Gated by cellular stress and injury, they open under pathophysiological conditions and in doing so release ‘danger signals’ including adenosine triphosphate into the extracellular environment. Linked to sterile inflammation via activation of the nod-like receptor protein 3 inflammasome, targeting aberrant hemichannel activity and the release of these danger signals has met with favourable outcomes in multiple models of disease, including secondary complications of diabetes. In this review, we provide a comprehensive update on those studies which document a role for aberrant connexin hemichannel activity in the pathogenesis of both diabetic eye and kidney disease, ahead of evaluating the efficacy of blocking connexin-43 specific hemichannels in these target tissues on tissue health and function.

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Empagliflozin reduces the senescence of cardiac stromal cells and improves cardiac function in a murine model of diabetes

Cited by 28 publications

References 46 publications

Empagliflozin Regulates the AdipoR1/p-AMPK/p-ACC Pathway to Alleviate Lipid Deposition in Diabetic Nephropathy

Empagliflozin Regulates the AdipoR1/p-AMPK/p-ACC Pathway to Alleviate Lipid Deposition in Diabetic Nephropathy

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

Connexin 43: A Target for the Treatment of Inflammation in Secondary Complications of the Kidney and Eye in Diabetes

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