RESUMEN
Sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) or gliflozins, are a new class of cardiovascular drugs with a proven clinical efficacy and a beneficial effect on prognosis in patients with heart failure with preserved ejection fraction (HFpEF). Impaired left ventricular (LV) diastolic function (DF) is an important element in the pathogenesis of HFpEF. Experimental studies have found intracellular mechanisms for the so-called diastolic effects in gliflozins. Studies using laboratory models of experimental HFpEF have demonstrated a positive effect of dapagliflozin and empagliflozin on the elastic properties of cardiomyocyte myofilaments, the dynamics of myocardial fibrosis, and intracellular sodium and calcium homeostasis. The significance of anti-inflammatory, antioxidant properties of gliflozins in improving the cardiomyocyte DF has been experimentally established. The effect of SGLT2 inhibitors on LV DF in patients at high risk for cardiovascular diseases and their complications, that has been demonstrated in relatively small clinical studies, is due to primary cardiac and secondary effects. Results of individual studies confirmed the protective (in relation to myocardial relaxation) properties of gliflozins in the conditions of a diastolic stress test. The regression of LV diastolic dysfunction associated with the SGLT2 inhibitor treatment found in small observational studies is important in the context of the significant beneficial effect of empagliflozin and dapagliflozin on the prognosis of cardiovascular diseases that has been demonstrated in large randomized clinical trials in patients with HFpEF.
Asunto(s)
Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Función Ventricular Izquierda/efectos de los fármacos , Función Ventricular Izquierda/fisiología , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/tratamiento farmacológico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Compuestos de Bencidrilo/farmacología , Compuestos de Bencidrilo/uso terapéutico , Glucósidos/farmacología , Glucósidos/uso terapéutico , Diástole/efectos de los fármacosRESUMEN
Patients with type 2 diabetes mellitus are frequently hospitalized for heart failure. The ratio of early diastolic mitral inflow velocity to early diastolic mitral annulus velocity (E/e'), measured by echocardiography, is a simple and convenient indicator of diastolic dysfunction. Various large clinical trials have reported that sodium glucose transporter-2 inhibitor therapy reduced cardiovascular events and hospitalizations in heart failure patients. We examined the effect of tofogliflozin on various physiological and cardiac function. A retrospective analysis was performed on elderly patients aged 65 years or older with type 2 diabetes mellitus attending Himi Municipal Hospital who were taking oral tofogliflozin 20 mg/day. Measurement of physiological and hormonal variables, blood sampling, and echocardiographic evaluations at 0, 1, 3, and 6 months were performed on those with ejection fraction (EF) of 40% or greater at the time of treatment. Statistical analysis was performed using t-tests and mixed-effects models, with brain natriuretic peptide less than or not less than 100 pg/mL, estimated glomerular filtration rate (eGFR) less than or not less than 50 mL/min/1.73 m2, and diuretics administered or not. Hypoglycemic effects were observed at 0, 1, 3, and 6 months. At each time point, EF was retained and E/e' was significantly reduced. On the other hand, most physiological parameters and laboratory results showed no clinical abnormalities. Mixed-effects models showed time-dependent reduction of E/e' in high/low brain natriuretic peptide, high/low eGFR, with or without diuretics between baseline and at 6 months. The interaction with time was significant in high/low eGFR. Tofogliflozin was shown to improve E/e', a measure of diastolic function, while maintaining EF, with hypoglycemic effects and no clinical side effects.
Asunto(s)
Compuestos de Bencidrilo , Diabetes Mellitus Tipo 2 , Glucósidos , Insuficiencia Cardíaca , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Volumen Sistólico , Humanos , Estudios Retrospectivos , Anciano , Masculino , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Compuestos de Bencidrilo/administración & dosificación , Compuestos de Bencidrilo/uso terapéutico , Compuestos de Bencidrilo/farmacología , Femenino , Glucósidos/administración & dosificación , Glucósidos/uso terapéutico , Glucósidos/farmacología , Volumen Sistólico/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/fisiopatología , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Anciano de 80 o más Años , Ecocardiografía , Tasa de Filtración Glomerular/efectos de los fármacosRESUMEN
Diabetes mellitus is a major public health concern, often leading to undiagnosed micro- and macrovascular complications, even in patients with controlled blood glucose levels. Recent evidence suggests that empagliflozin and metformin have renoprotective effects in addition to their hypoglycemic action. This study investigated the potential protective effect of empagliflozin and metformin on diabetic renal complications. Forty-two adult male Sprague Dawley rats were randomized into six groups: normal control, diabetic control, metformin (250 mg/kg), empagliflozin (10 mg/kg), and combination therapy groups. Type 2 diabetes was induced in rats by a single intraperitoneal injection of streptozotocin (40 mg/kg) following two weeks of 10% fructose solution in their drinking water. Blood glucose, creatinine, urea nitrogen, inflammatory markers (IL-6, TNF-α), and renal tissue caspase-3 were assessed after eight weeks. Blood glucose, urea, creatinine, serum IL-6, TNF-α, and tissue caspase-3 were significantly decreased in the treatment groups compared to the diabetic group. The histopathological findings revealed that treatment with empagliflozin and/or metformin improved the damage in the renal tissue caused by diabetes-induced nephropathy. Moreover, co-administration of empagliflozin and metformin resulted in even better outcomes. Our data revealed that empagliflozin and metformin could improve renal function and decrease inflammation and apoptosis in diabetic animals, delaying the progression of diabetic nephropathy. Combined treatment with metformin and empagliflozin proved to have an additive protective action on renal tissue.
Asunto(s)
Compuestos de Bencidrilo , Diabetes Mellitus Experimental , Nefropatías Diabéticas , Glucósidos , Metformina , Ratas Sprague-Dawley , Metformina/farmacología , Metformina/uso terapéutico , Compuestos de Bencidrilo/farmacología , Compuestos de Bencidrilo/uso terapéutico , Animales , Glucósidos/farmacología , Glucósidos/uso terapéutico , Glucósidos/administración & dosificación , Masculino , Ratas , Nefropatías Diabéticas/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Quimioterapia Combinada , Glucemia , Riñón/efectos de los fármacos , Riñón/patologíaRESUMEN
A previous study showed that high-glucose (HG) conditions induce mitochondria fragmentation through the calcium-mediated activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) in H9C2 cells. This study tested whether empagliflozin could prevent HG-induced mitochondria fragmentation through this pathway. We found that exposing H9C2 cells to an HG concentration decreased cell viability and increased cell apoptosis and caspase-3. Empagliflozin could reverse the apoptosis effect of HG stimulation on H9C2 cells. In addition, the HG condition caused mitochondria fragmentation, which was reduced by empagliflozin. The expression of mitochondria fission protein was upregulated, and fusion proteins were downregulated under HG stimulation. The expression of fission proteins was decreased under empagliflozin treatment. Increased calcium accumulation was observed under the HG condition, which was decreased by empagliflozin. The increased expression of ERK 1/2 under HG stimulation was also reversed by empagliflozin. Our study shows that empagliflozin could reverse the HG condition, causing a calcium-dependent activation of the ERK 1/2 pathway, which caused mitochondria fragmentation in H9C2 cells.
Asunto(s)
Apoptosis , Compuestos de Bencidrilo , Calcio , Glucosa , Glucósidos , Sistema de Señalización de MAP Quinasas , Mitocondrias , Apoptosis/efectos de los fármacos , Compuestos de Bencidrilo/farmacología , Glucósidos/farmacología , Glucosa/metabolismo , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Calcio/metabolismo , Animales , Ratas , Línea Celular , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Dinámicas Mitocondriales/efectos de los fármacos , Caspasa 3/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismoRESUMEN
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have a variety of cardiovascular and renoprotective effects and have been developed as novel agents for the treatment of heart failure. However, the beneficial mechanisms of SGLT2i on cardiac tissue need to be investigated further. In this study, we established a mouse model of acute myocardial infarction (AMI) using coronary artery constriction surgery and investigated the role of dapagliflozin (DAPA) in protecting cardiomyocytes from hypoxic injury induced by AMI. In vitro experiments were done using hypoxic cultured H9c2 ventricular cells to verify this potential mechanism. Expression of the SIRT family and related genes and proteins was verified by qPCR, Western blotting and immunofluorescence staining, and the intrinsic potential mechanism of cardiomyocyte death due to AMI and hypoxia was comprehensively investigated by RNA sequencing. The RNA sequencing results of cardiomyocytes from AMI mice showed that the SIRT family may be mainly involved in the mechanisms of hypoxia-induced cardiomyocyte death. In vitro hypoxia-induced ventricular cells showed the role of dapagliflozin in conferring resistance to hypoxic injury in cardiomyocytes. It showed that SIRT1/3/6 were downregulated in H9c2 cells in a hypoxic environment, and the addition of dapagliflozin significantly increased the gene and protein expression of SIRT1, 3 and 6. We then verified the underlying mechanisms induced by dapagliflozin in hypoxic cardiomyocytes using RNA-seq, and found that dapagliflozin upregulated the hypoxia-induced gene downregulation, which includes ESRRA, EPAS1, AGTRAP, etc., that associated with SIRTs-related and apoptosis-related signaling to prevent H9c2 cell death. This study provides laboratory data for SGLT2i dapagliflozin treatment of AMI and confirms that dapagliflozin can be used to treat hypoxia-induced cellular necrosis in cardiomyocytes, in which SIRT1 and SIRT3 may play an important role. This opens up further opportunities for SGLT2i in the treatment of heart disease.
Asunto(s)
Compuestos de Bencidrilo , Glucósidos , Infarto del Miocardio , Miocitos Cardíacos , Transducción de Señal , Sirtuina 1 , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Glucósidos/farmacología , Glucósidos/uso terapéutico , Animales , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Compuestos de Bencidrilo/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Ratones , Infarto del Miocardio/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Sirtuina 1/metabolismo , Sirtuina 1/genética , Transducción de Señal/efectos de los fármacos , Masculino , Sirtuina 3/metabolismo , Sirtuina 3/genética , Sirtuinas/metabolismo , Sirtuinas/genética , Línea Celular , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Hipoxia de la Célula/efectos de los fármacos , Ratas , Apoptosis/efectos de los fármacosRESUMEN
Diabetes mellitus is a metabolic disorder caused by a dysfunction in insulin action or secretion, leading to an elevation in blood glucose levels. It is a highly prevalent condition and as a result, the NHS spends 10 % of its entire budget on diabetes mellitus care, that is equivalent to £10 billion a year. Diabetes mellitus has been linked with vascular and neurological complications which may be associated with the progression of neurodegeneration and Alzheimer's disease. Chronic hyperglycaemia increases the production of the reactive oxidant species (ROS) such as methylglyoxal (MGO). MGO has been linked with vascular complications, neuropathy and cytotoxicity. The main aim of this study was to investigate the potential beneficial effect of antidiabetic agents such as metformin and dapagliflozin on human brain neuronal cells (SH-SY5Y) treated with MGO. SH-SY5Y cells were cultured in DMEM/F12 media and subjected overnight incubation with one of the following treatment conditions: Control (untreated); MGO (1 µM); MGO (100 µM); metformin (100 µM) + MGO (100 µM); and dapagliflozin (10 µM) + MGO (100 µM). Several assays were conducted to explore the effect of the treatment groups on the SH-SY5Y cells. These included: MTT assay; LDH assay, peroxynitrite fluorescence assay, and laser scanning confocal microscopy. MGO (100 µM) led to significant cell injury and damage and significantly reduced the survival of the cells by approximately 50-75 %, associated with significant increase in peroxynitrite. The addition of metformin (100 µM) or dapagliflozin (10 µM) represented significant protective effects on the cells and prevented the cell damage caused by the high MGO concentration. As a result, the findings of this research reveal that MGO-induced cell damage may partly be mediated by the generation of peroxynitrite, while the antidiabetic agents such as metformin and dapagliflozin prevent brain cell death, which potentially may play prophylactic roles against the risk of dementia in diabetic patients.
Asunto(s)
Compuestos de Bencidrilo , Glucósidos , Hipoglucemiantes , Metformina , Neuronas , Piruvaldehído , Humanos , Compuestos de Bencidrilo/farmacología , Piruvaldehído/toxicidad , Metformina/farmacología , Glucósidos/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Hipoglucemiantes/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/citología , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neuroblastoma/patología , Neuroblastoma/metabolismoRESUMEN
Beneficial effects of sodium glucose co-transporter 2 inhibitors (SGLT2is) in cardiovascular diseases have been extensively reported leading to the inclusion of these drugs in the treatment guidelines for heart failure. However, molecular actions especially on non-myocyte cells remain uncertain. We observed dose-dependent inhibitory effects of two SGLT2is, dapagliflozin (DAPA) and empagliflozin (EMPA), on inflammatory signaling in human umbilical vein endothelial cells. Proteomic analyses and subsequent enrichment analyses discovered profound effects of these SGLT2is on proteins involved in mitochondrial respiration and actin cytoskeleton. Validation in functional oxygen consumption measurements as well as tube formation and migration assays revealed strong impacts of DAPA. Considering that most influenced parameters played central roles in endothelial to mesenchymal transition (EndMT), we performed in vitro EndMT assays and identified substantial reduction of mesenchymal and fibrosis marker expression as well as changes in cellular morphology upon treatment with SGLT2is. In line, human cardiac fibroblasts exposed to DAPA showed less proliferation, reduced ATP production, and decelerated migration capacity while less extensive impacts were observed upon EMPA. Mechanistically, sodium proton exchanger 1 (NHE1) as well as sodium-myoinositol cotransporter (SMIT) and sodium-multivitamin cotransporter (SMVT) could be identified as relevant targets of SGLT2is in non-myocyte cardiovascular cells as validated by individual siRNA-knockdown experiments. In summary, we found comprehensive beneficial effects of SGLT2is on human endothelial cells and cardiac fibroblasts. The results of this study therefore support a distinct effect of selected SGLT2i on non-myocyte cardiovascular cells and grant further insights into potential molecular mode of action of these drugs.
Asunto(s)
Compuestos de Bencidrilo , Fibroblastos , Glucósidos , Células Endoteliales de la Vena Umbilical Humana , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Compuestos de Bencidrilo/farmacología , Glucósidos/farmacología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Intercambiador 1 de Sodio-Hidrógeno/metabolismo , Intercambiador 1 de Sodio-Hidrógeno/antagonistas & inhibidores , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacosRESUMEN
It has been suggested that sodium-glucose cotransporter 2 (SGLT2) inhibitors have cardioprotective effects during myocardial ischemia/reperfusion (I/R) independent of glucose-lowering action. However, the effects of SGLT2 inhibitors on structural damage to cardiomyocytes in the ischemic region during I/R remain unknown. We applied a microdialysis technique to the heart of anesthetized rats and investigated the effects of an SGLT2 inhibitor, dapagliflozin, on myocardial interstitial myoglobin levels in the ischemic region during coronary occlusion followed by reperfusion. Dapagliflozin was administered systemically (40 µg/body iv) or locally via a dialysis probe (100 µM and 1 mM) 30 min before coronary occlusion. In the vehicle group, coronary occlusion increased the dialysate myoglobin concentration in the ischemic region. Reperfusion further increased the dialysate myoglobin concentration. Intravenous administration of dapagliflozin reduced dialysate myoglobin concentration during ischemia and at 0-15 min after reperfusion, but local administration (100 µM and 1 mM) did not. Therefore, acute systemic administration of dapagliflozin prior to ischemia has cardioprotective effects on structural damage during I/R.
Asunto(s)
Compuestos de Bencidrilo , Glucósidos , Daño por Reperfusión Miocárdica , Miocitos Cardíacos , Mioglobina , Animales , Compuestos de Bencidrilo/farmacología , Mioglobina/metabolismo , Glucósidos/farmacología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Ratas , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Masculino , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , MicrodiálisisRESUMEN
Dapagliflozin is a pharmacological drug commonly used to manage type 2 diabetes by inhibiting the sodium-glucose cotransporter in the proximal renal tubules. The primary objective of this research was to develop a topical ointment formulation containing dapagliflozin and assess its efficacy in treating psoriasis using an imiquimod-induced psoriasis model. A total of 16 Swiss albino mice, with weights ranging from 24 to 30 grams, were allocated randomly into six groups, each group including ten animals. The study assessed the effects of various concentrations of dapagliflozin ointment on levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8), IL-17, and IL-37, as well as on erythema, scaling, and epidermal thickness. Dapagliflozin ointment significantly reduced these cytokine levels and disease scores, indicating anti-psoriatic and anti-inflammatory properties. Therefore, when applied topically, dapagliflozin ointment had strong efficacy against imiquimod-induced psoriatic skin inflammation, suggesting its potential as a novel therapeutic option for psoriasis treatment.
Asunto(s)
Compuestos de Bencidrilo , Modelos Animales de Enfermedad , Glucósidos , Imiquimod , Pomadas , Psoriasis , Psoriasis/tratamiento farmacológico , Psoriasis/inducido químicamente , Psoriasis/patología , Animales , Glucósidos/farmacología , Glucósidos/uso terapéutico , Glucósidos/administración & dosificación , Ratones , Compuestos de Bencidrilo/farmacología , Citocinas/metabolismo , MasculinoRESUMEN
Heart failure with preserved ejection fraction (HFpEF) is a mortal clinical syndrome without effective therapies. Empagliflozin (EMPA) improves cardiovascular outcomes in HFpEF patients, but the underlying mechanism remains elusive. Here, mice were fed a high-fat diet (HFD) supplemented with L-NAME for 12 weeks and subsequently intraperitoneally injected with EMPA for another 4 weeks. A 4D-DIA proteomic assay was performed to detect protein changes in the failing hearts. We identified 310 differentially expressed proteins (DEPs) (ctrl vs. HFpEF group) and 173 DEPs (HFpEF vs. EMPA group). The regulation of immune system processes was enriched in all groups and the interferon response genes (STAT1, Ifit1, Ifi35 and Ifi47) were upregulated in HFpEF mice but downregulated after EMPA administration. In addition, EMPA treatment suppressed the increase in the levels of aging markers (p16 and p21) in HFpEF hearts. Further bioinformatics analysis verified STAT1 as the hub transcription factor during pathological changes in HFpEF mice. We next treated H9C2 cells with IFN-γ, a primary agonist of STAT1 phosphorylation, to investigate whether EMPA plays a beneficial role by blocking STAT1 activation. Our results showed that IFN-γ treatment caused cardiomyocyte senescence and STAT1 activation, which were inhibited by EMPA administration. Notably, STAT1 inhibition significantly reduced cellular senescence possibly by regulating STING expression. Our findings revealed that EMPA mitigates cardiac inflammation and aging in HFpEF mice by inhibiting STAT1 activation. The STAT1-STING axis may act as a pivotal mechanism in the pathogenesis of HFpEF, especially under inflammatory and aging conditions.
Asunto(s)
Compuestos de Bencidrilo , Senescencia Celular , Modelos Animales de Enfermedad , Glucósidos , Insuficiencia Cardíaca , Proteínas de la Membrana , Ratones Endogámicos C57BL , Miocitos Cardíacos , Factor de Transcripción STAT1 , Transducción de Señal , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Volumen Sistólico , Función Ventricular Izquierda , Animales , Factor de Transcripción STAT1/metabolismo , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/prevención & control , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/patología , Compuestos de Bencidrilo/farmacología , Glucósidos/farmacología , Senescencia Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Masculino , Volumen Sistólico/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Línea Celular , Interferón gamma/metabolismo , Fosforilación , RatonesRESUMEN
BACKGROUND: Extracellular matrix (ECM) stiffness is closely related to the progress of diabetic cardiomyopathy (DCM) and the response of treatment of DCM to anti-diabetic drugs. Dapagliflozin (Dapa) has been proven to have cardio-protective efficacy for diabetes and listed as the first-line drug to treat heart failure. But the regulatory relationship between ECM stiffness and treatment efficacy of Dapa remains elusive. MATERIALS AND METHODS: This work investigated the effect of ECM stiffness on DCM progression and Dapa efficacy using both in vivo DCM rat model and in vitro myocardial cell model with high glucose injury. First, through DCM rat models with various levels of myocardial injury and administration with Dapa treatment for four weeks, the levels of myocardial injury, myocardial oxidative stress, expressions of AT1R (a mechanical signal protein) and the stiffness of myocardial tissues were obtained. Then for mimicking the stiffness of myocardial tissues at early and late stages of DCM, we constructed cell models through culturing H9c2 myocardial cells on the polyacrylamide gels with two stiffness and exposed to a high glucose level and without/with Dapa intervention. The cell viability, reactive oxygen species (ROS) levels and expressions of mechanical signal sensitive proteins were obtained. RESULTS: The DCM progression is accompanied by the increased myocardial tissue stiffness, which can synergistically exacerbate myocardial cell injury with high glucose. Dapa can improve the ECM stiffness-induced DCM progression and its efficacy on DCM is more pronounced on the soft ECM, which is related to the regulation pathway of AT1R-FAK-NOX2. Besides, Dapa can inhibit the expression of the ECM-induced integrin ß1, but without significant impact on piezo 1. CONCLUSIONS: Our study found the regulation and effect of biomechanics in the DCM progression and on the Dapa efficacy on DCM, providing the new insights for the DCM treatment. Additionally, our work showed the better clinical prognosis of DCM under early Dapa intervention.
Asunto(s)
Compuestos de Bencidrilo , Cardiomiopatías Diabéticas , Matriz Extracelular , Glucósidos , Miocitos Cardíacos , Estrés Oxidativo , Ratas Sprague-Dawley , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Cardiomiopatías Diabéticas/fisiopatología , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/patología , Glucósidos/farmacología , Matriz Extracelular/metabolismo , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/patología , Compuestos de Bencidrilo/farmacología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Miocitos Cardíacos/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Masculino , Estrés Oxidativo/efectos de los fármacos , Línea Celular , Modelos Animales de Enfermedad , Especies Reactivas de Oxígeno/metabolismo , Ratas , Quinasa 1 de Adhesión Focal/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicacionesRESUMEN
A bidirectional relationship exists between atrial fibrillation (AF) and kidney function. Uncontrolled AF may lead to kidney injury, whereas renal dysfunction may contribute to AF initiation and maintenance. This study aimed to investigate the protective effect of the sodium glucose cotransporter-2 inhibitor empagliflozin (EMPA) on acute kidney injury (AKI) associated with AF induced by acetylcholine and calcium chloride (ACh/CaCl2) in rats and elucidate the potential underlying mechanism. Rats were randomly divided as follows: control (CTRL) group: administered vehicles only; AF group: intravenously injected 1â¯ml/kg of an ACh/CaCl2 mixture for seven days to induce AF; EMPA group: orally administered EMPA (30â¯mg/kg) for seven days; AF+EMPA10 and AF+EMPA30 groups: co-administered the induction mixture and EMPA (10 and 30â¯mg/kg, respectively) for seven days. Our results showed that EMPA (10 and 30â¯mg/kg) effectively maintained kidney function and demonstrated a significant antioxidant potential. EMPA also suppressed AF-induced renal tubulointerstitial injury and fibrotic changes concurrently with reducing renal levels of the pro-inflammatory cytokines tumour necrosis factor-α (TNF-α) and interleukin-6, as well as the pro-fibrotic marker transforming growth factor beta-1 and collagen type I. Mechanistically, EMPA boosted nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) renal tissue expression while repressing nuclear factor kappa B (NF-κB) activation. In addition, these beneficial effects of EMPA on kidneys were concurrent with its ability to effectively inhibit AF-related electrocardiographic changes, reduce incidence and duration of AF episodes, and markedly suppress serum B-type natriuretic peptide and C-reactive protein levels. In conclusion, EMPA protected against AKI associated with AF induced by ACh/CaCl2 in rats through simultaneous modulation of the Nrf2/HO-1 and the NF-κB/TNF-α signaling pathways, exerting antioxidant, anti-inflammatory, and anti-fibrotic effects.
Asunto(s)
Lesión Renal Aguda , Fibrilación Atrial , Compuestos de Bencidrilo , Glucósidos , Factor 2 Relacionado con NF-E2 , FN-kappa B , Transducción de Señal , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Factor de Necrosis Tumoral alfa , Animales , Glucósidos/farmacología , Glucósidos/uso terapéutico , Factor 2 Relacionado con NF-E2/metabolismo , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/etiología , FN-kappa B/metabolismo , Compuestos de Bencidrilo/farmacología , Masculino , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Fibrilación Atrial/prevención & control , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/etiología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Ratas , Ratas Sprague-Dawley , Hemo Oxigenasa (Desciclizante)/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patologíaRESUMEN
Lipid peroxidation and mitochondrial damage impair insulin sensitivity in skeletal muscle. Sirtuin-1 (SIRT1) protects mitochondria and activates under energy restriction. Dapagliflozin (Dapa) is an antihyperglycaemic agent that belongs to the sodium-glucose cotransporter-2 (SGLT2) inhibitors. Evidence shows that Dapa can induce nutrient deprivation effects, providing additional metabolic benefits. This study investigates whether Dapa can trigger nutrient deprivation to activate SIRT1 and enhance insulin sensitivity in skeletal muscle. We treated diet-induced obese (DIO) mice with Dapa and measured metabolic parameters, lipid accumulation, oxidative stress, mitochondrial function, and glucose utilization in skeletal muscle. ß-hydroxybutyric acid (ß-HB) was intervened in C2C12 myotubes. The role of SIRT1 was verified by RNA interference. We found that Dapa treatment induced nutrient deprivation state and reduced lipid deposition and oxidative stress, improved mitochondrial function and glucose tolerance in skeletal muscle. The same positive effects were observed after ß-HB intervening for C2C12 myotubes, and the promoting effects on glucose utilization were diminished by SIRT1 RNA interference. Thus, Dapa promotes a nutrient deprivation state and enhances skeletal muscle insulin sensitivity via SIRT1 activation. In this study, we identified a novel hypoglycemic mechanism of Dapa and the potential mechanistic targets.
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Compuestos de Bencidrilo , Glucósidos , Resistencia a la Insulina , Músculo Esquelético , Estrés Oxidativo , Sirtuina 1 , Animales , Sirtuina 1/metabolismo , Sirtuina 1/genética , Glucósidos/farmacología , Músculo Esquelético/metabolismo , Músculo Esquelético/efectos de los fármacos , Ratones , Compuestos de Bencidrilo/farmacología , Estrés Oxidativo/efectos de los fármacos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/efectos de los fármacos , Masculino , Glucosa/metabolismo , Línea Celular , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Ratones Endogámicos C57BL , Ácido 3-Hidroxibutírico/farmacología , Ácido 3-Hidroxibutírico/metabolismo , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Hipoglucemiantes/farmacologíaRESUMEN
BACKGROUND AND AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) can ameliorate arrhythmias; however, the mechanisms underlying their antiarrhythmic effect remain unclear. Therefore, we aimed to test the hypothesis that the SGLT2i empagliflozin (EMPA) ameliorates ventricular arrhythmias caused by myocardial infarction (MI) by inhibiting sympathetic remodeling. METHODS: Male nondiabetic Sprague-Dawley rats were divided into Sham ( n â=â10), MI ( n â=â13), low-EMPA (10âmg/kg/day; n â=â13), and high-EMPA (30âmg/kg/day; n â=â13) groups. Except for the Sham group, MI models were established by ligation of the left anterior descending coronary artery. After 4 weeks, the hearts were removed. Echocardiography, electrical stimulation, hematoxylin-eosin staining and Masson's staining, Western blotting, immunohistochemistry (IHC), and ELISA were performed. RESULTS: Except for left ventricular posterior wall thickness (LVPWT), EMPA treatment significantly ameliorated the left ventricular anterior wall thickness (LVAWT), interventricular septum thickness (IVST), left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), and left ventricular ejection fraction (LVEF) in MI rats; there was no statistical difference between the low-EMPA and high-EMPA groups. The threshold for ventricular fibrillation induction and myocardial fibrosis was significantly ameliorated in EMPA-treated rats, and there was no statistical difference between the high-EMPA and low-EMPA groups. EMPA decreased the expression of nerve growth factor (NGF), tyrosine kinase receptor A (TrkA), tyrosine hydroxylase, and growth-associated protein 43 (GAP43) in the left ventricular infarction margin myocardium of MI rats, especially in the high-EMPA group, with a statistically significant difference between the high-EMPA and low-EMPA groups. High-EMPA significantly decreased noradrenaline (NE) levels in the blood of MI rats; however, there was no statistical difference between the low-EMPA and MI groups. CONCLUSION: EMPA ameliorated the occurrence of ventricular arrhythmias in MI rats, which may be related to a reduction in sympathetic activity, inhibition of the NGF/TrkA pathway, inhibition of sympathetic remodeling, and improvement in cardiac function and cardiac structural remodeling.
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Compuestos de Bencidrilo , Modelos Animales de Enfermedad , Glucósidos , Infarto del Miocardio , Factor de Crecimiento Nervioso , Ratas Sprague-Dawley , Transducción de Señal , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Sistema Nervioso Simpático , Remodelación Ventricular , Animales , Masculino , Compuestos de Bencidrilo/farmacología , Glucósidos/farmacología , Factor de Crecimiento Nervioso/metabolismo , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/complicaciones , Infarto del Miocardio/patología , Infarto del Miocardio/metabolismo , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiopatología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Remodelación Ventricular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Receptor trkA/metabolismo , Receptor trkA/antagonistas & inhibidores , Proteína GAP-43/metabolismo , Función Ventricular Izquierda/efectos de los fármacos , Arritmias Cardíacas/etiología , Arritmias Cardíacas/prevención & control , Arritmias Cardíacas/fisiopatología , Arritmias Cardíacas/tratamiento farmacológico , Ratas , Antiarrítmicos/farmacología , Conexina 43RESUMEN
Inhibitors of sodium/glucose cotransporter 2 (SGLT2), such as empagliflozin and canagliflozin, have been widely used to block glucose reabsorption in the proximal tubules of kidneys in patients with diabetes. A meta-analysis suggested that SGLT2 inhibitors are associated with a decreased risk of asthma development. Therefore, we investigated whether SGLT2 inhibitors could suppress allergic asthma. Empagliflozin and canagliflozin suppressed the in vitro degranulation reaction induced by antigens in a concentration-dependent manner in RBL-2H3 mast cells. Empagliflozin and canagliflozin were administered to BALB/c mice sensitized to ovalbumin (OVA). The administration of empagliflozin or canagliflozin significantly suppressed OVA-induced airway hyper-responsiveness and increased the number of immune cells and pro-inflammatory cytokine mRNA expression levels in bronchoalveolar lavage fluid. The administration of empagliflozin and canagliflozin also suppressed OVA-induced histopathological changes in the lungs. Empagliflozin and canagliflozin also suppressed serum IgE levels. These results suggested that empagliflozin and canagliflozin may be applicable for the treatment of allergic asthma by suppressing immune responses.
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Asma , Compuestos de Bencidrilo , Canagliflozina , Glucósidos , Ratones Endogámicos BALB C , Ovalbúmina , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Canagliflozina/farmacología , Canagliflozina/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Asma/tratamiento farmacológico , Asma/inmunología , Glucósidos/farmacología , Glucósidos/uso terapéutico , Compuestos de Bencidrilo/farmacología , Compuestos de Bencidrilo/uso terapéutico , Ratones , Ovalbúmina/efectos adversos , Pulmón/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Mastocitos/inmunología , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Líquido del Lavado Bronquioalveolar , Ratas , Citocinas/metabolismo , Degranulación de la Célula/efectos de los fármacos , Modelos Animales de Enfermedad , Transportador 2 de Sodio-Glucosa/metabolismo , MasculinoRESUMEN
We explored physiological effects of the sodium-glucose co-transporter-2 inhibitor empagliflozin on intact experimentally hypertrophic murine hearts following transverse aortic constriction (TAC). Postoperative drug (2-6 weeks) challenge resulted in reduced late Na+ currents, and increased phosphorylated (p-)CaMK-II and Nav1.5 but not total (t)-CaMK-II, and Na+/Ca2+ exchanger expression, confirming previous cardiomyocyte-level reports. It rescued TAC-induced reductions in echocardiographic ejection fraction and fractional shortening, and diastolic anterior and posterior wall thickening. Dual voltage- and Ca2+-optical mapping of Langendorff-perfused hearts demonstrated that empagliflozin rescued TAC-induced increases in action potential durations at 80% recovery (APD80), Ca2+ transient peak signals and durations at 80% recovery (CaTD80), times to peak Ca2+ (TTP100) and Ca2+ decay constants (Decay30-90) during regular 10-Hz stimulation, and Ca2+ transient alternans with shortening cycle length. Isoproterenol shortened APD80 in sham-operated and TAC-only hearts, shortening CaTD80 and Decay30-90 but sparing TTP100 and Ca2+ transient alternans in all groups. All groups showed similar APD80, and TAC-only hearts showed greater CaTD80, heterogeneities following isoproterenol challenge. Empagliflozin abolished or reduced ventricular tachycardia and premature ventricular contractions and associated re-entrant conduction patterns, in isoproterenol-challenged TAC-operated hearts following successive burst pacing episodes. Empagliflozin thus rescues TAC-induced ventricular hypertrophy and systolic functional, Ca2+ homeostatic, and pro-arrhythmogenic changes in intact hearts.
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Compuestos de Bencidrilo , Calcio , Glucósidos , Homeostasis , Animales , Compuestos de Bencidrilo/farmacología , Glucósidos/farmacología , Ratones , Calcio/metabolismo , Homeostasis/efectos de los fármacos , Masculino , Potenciales de Acción/efectos de los fármacos , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Canal de Sodio Activado por Voltaje NAV1.5/metabolismo , Intercambiador de Sodio-Calcio/metabolismo , Aorta/efectos de los fármacos , Aorta/metabolismo , Aorta/cirugía , Ratones Endogámicos C57BL , Isoproterenol/farmacología , Modelos Animales de EnfermedadAsunto(s)
Autofagia , Compuestos de Bencidrilo , Senescencia Celular , Glucósidos , Imidazoles , Miocitos Cardíacos , Piridazinas , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Miocitos Cardíacos/metabolismo , Senescencia Celular/efectos de los fármacos , Autofagia/efectos de los fármacos , Compuestos de Bencidrilo/farmacología , Animales , Imidazoles/farmacología , Piridazinas/farmacología , Glucósidos/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal/efectos de los fármacos , Células Cultivadas , RatasRESUMEN
BACKGROUND: Patients with diabetes are prone to acute kidney injury (AKI) with a high mortality rate, poor prognosis, and a higher risk of progression to chronic kidney disease than non-diabetic patients. METHODS: Streptozotocin (STZ)-treated type 1 and db/db type 2 diabetes model were established, AKI model was induced in mice by ischemia-reperfusion injury(IRI). Mouse proximal tubular cell cells were subjected to high glucose and hypoxia-reoxygenation in vitro. Transcriptional RNA sequencing was performed for clustering analysis and target gene screening. Renal structural damage was determined by histological staining, whereas creatinine and urea nitrogen levels were used to measure renal function. RESULTS: Deteriorated renal function and renal tissue damage were observed in AKI mice with diabetic background. RNA sequencing showed a decrease in fatty acid oxidation (FAO) pathway and an increase in abnormal glycolysis. Treatment with Dapa, Sitagliptin(a DPP-4 inhibitor)and insulin reduced blood glucose levels in mice, and improved renal function. However, Dapa had a superior therapeutic effect and alleviated aberrant FAO and glycosis. Dapa reduced cellular death in cultured cells under high glucose hypoxia-reoxygenation conditions, alleviated FAO dysfunction, and reduced abnormal glycolysis. RNA sequencing showed that SIRT3 expression was reduced in diabetic IRI, which was largely restored by Dapa intervention. 3-TYP, a SIRT3 inhibitor, reversed the renal protective effects of Dapa and mediated abnormal FAO and glycolysis in mice and tubular cells. CONCLUSION: Our study provides experimental evidence for the use of Dapa as a means to reduce diabetic AKI by ameliorating metabolic reprogramming in renal tubular cells.
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Lesión Renal Aguda , Compuestos de Bencidrilo , Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Glucósidos , Reprogramación Metabólica , Insuficiencia Renal Crónica , Animales , Masculino , Ratones , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/patología , Lesión Renal Aguda/etiología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/patología , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/patología , Glucósidos/farmacología , Glucósidos/uso terapéutico , Reprogramación Metabólica/efectos de los fármacos , Ratones Endogámicos C57BL , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/patología , Transducción de Señal/efectos de los fármacos , Sirtuina 3/metabolismo , Sirtuina 3/genética , Compuestos de Bencidrilo/farmacología , Compuestos de Bencidrilo/uso terapéuticoRESUMEN
Acetaminophen (APAP) is one of the most clinically relevant medications associated with acute liver damage. A prolific deal of research validated the hepatoprotective effect of empagliflozin (EMPA); however, its effect on APAP-induced hepatotoxicity has still not been investigated. In this study, the prospective hepatoprotective impact of EMPA against APAP-induced hepatotoxicity was investigated. Twenty-eight Balb-C mice were assigned to four groups: control, APAP, EMPA10/APAP, and EMPA25/APAP. At the end of the experiment, serum hepatotoxicity biomarkers, MDA level, and GSH content were estimated. Hepatic mitofusin-2 (MFN2), optic atrophy 1 (OPA1), dynamin-related protein 1 (Drp1), and mitochondrial fission 1 protein (FIS1) were immunoassayed. PGC-1α, cGAS, and STING mRNA expression were assessed by real-time PCR. Histopathological changes and immunohistochemistry of INF-ß, p-NF-κB, and iNOS were evaluated. APAP treatment caused significant hepatic functional impairment and increased hepatic MDA levels, as well as a concomitant decrease in GSH content. Marked elevation in Drp1 and FIS1 levels, INF-ß, p-NF-κB, and iNOS immunoreactivity, and reduction in MFN2 and OPA1 levels in the APAP-injected group, PGC-1α downregulation, and high expression of cGAS and STING were also documented. EMPA effectively ameliorated APAP-generated structural and functional changes in the liver, restored redox homeostasis and mitochondrial dynamics balance, and enhanced mitochondrial biogenesis, remarkably diminished hepatic expression of cGAS and STING, and elicited a reduction in hepatic inflammation. Moreover, the computational modeling data support the interaction of APAP with antioxidant system-related proteins as well as the interactions of EMPA against Drp1, cGAS, IKKA, and iNOS proteins. Our findings demonstrated for the first time that EMPA has an ameliorative impact against APAP-induced hepatotoxicity in mice via modulation of mitochondrial dynamics, biogenesis, and cGAS/STING-dependent inflammation. Thus, this study concluded that EMPA could be a promising therapeutic modality for acute liver toxicity.
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Acetaminofén , Compuestos de Bencidrilo , Enfermedad Hepática Inducida por Sustancias y Drogas , Dinaminas , GTP Fosfohidrolasas , Glucósidos , Proteínas de la Membrana , Dinámicas Mitocondriales , Nucleotidiltransferasas , Animales , Masculino , Ratones , Acetaminofén/toxicidad , Acetaminofén/efectos adversos , Compuestos de Bencidrilo/farmacología , Compuestos de Bencidrilo/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Dinaminas/metabolismo , Dinaminas/genética , Glucósidos/farmacología , GTP Fosfohidrolasas/metabolismo , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Ratones Endogámicos BALB C , Dinámicas Mitocondriales/efectos de los fármacos , Proteínas Mitocondriales/metabolismo , FN-kappa B/metabolismo , Nucleotidiltransferasas/metabolismo , Biogénesis de Organelos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Recently, podocyte mitochondrial dysfunction and necroptosis have been shown to play critical roles in renal fibrosis (RF) in diabetic kidney disease (DKD); however, these conditions lack effective treatment. In China, the supplemented Gegen Qinlian Decoction Formula (SGQDF), which originates from the classical prescription Gegen Qinlian Decoction, has been widely used to treat patients with DKD. However, it remains unclear whether SGQDF alleviates podocyte injury-associated RF in patients with DKD. AIM OF STUDY: This study aimed to clarify the therapeutic effects of SGQDF compared with those of empagliflozin (EMPA) on podocyte mitochondrial fission and RF in DKD and its necroptosis-related mechanisms. MATERIALS AND METHODS: Modified DKD rat models were developed through a combination of uninephrectomy, streptozotocin administration through intraperitoneal injection, and exposure to a high-fat diet. Following RF formation, the DKD rat models received either a high dose of SGQDF (H-SGQDF), a low dose of SGQDF (L-SGQDF), EMPA, or vehicle for 4 weeks. In our in vitro study, we subjected cultured murine podocytes to a high-glucose environment and various treatments including Mdivi-1, adalimumab, and necrostatin-1, with or without H-SGQDF or EMPA. SGQDF target prediction and molecular docking verification were performed. For the in vivo study, we focused on examining changes in the parameters associated with renal injury, RF, and oxidative stress (OS)-induced injuries in podocytes. Both in vivo and in vitro studies included an analysis of changes in podocyte mitochondrial fission, TNF-α-induced podocyte necroptosis, and the RIPK1/RIPK3/MLKL signaling pathway activation. RESULTS: SGQDF improved renal injury markers, including body weight, blood glucose, serum creatinine, blood urea nitrogen, and urinary albumin, in a dose-dependent manner. The beneficial effects of H-SGQDF in vivo were greater than those of L-SGQDF alone in vivo. Interestingly, similar to EMPA, H-SGQDF ameliorated RF and reduced OS-induced podocyte injury in diabetic kidneys. Furthermore, TNF-α signaling was shown to be important in the network construction of "the SGQDF-component-target." Based on this, we also showed that the beneficial effects in vivo and in vitro of H-SGQDF were closely related to the improvement in mitochondrial dysfunction and the inhibition of TNF-α-induced necroptosis in podocytes. CONCLUSION: In the present study, we showed that H-SGQDF, similar to EMPA, attenuates podocyte mitochondrial fission and RF, and that the underlying therapeutic mechanisms are closely related to inhibiting the activation of the RIPK1/RIPK3/MLKL signaling axis in diabetic kidneys. Our findings provide new pharmacological evidence for the application of H-SGQDF in the RF treatment of DKD.