The Na/K-ATPase Signaling and SGLT2 Inhibitor-Mediated Cardiorenal Protection: A Crossed Road?
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ABSTRACT:
SUBMITTER: Liu J
PROVIDER: S-EPMC8595165 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Recent clinical trial data suggest a cardiorenal protective effect of sodium glucose cotransporter 2 (SGLT2) inhibition. We demonstrate that chemical denervation in neurogenic hypertensive Schlager (BPH/2J) mice reduced blood pressure, improved glucose homeostasis, and reduced renal SGLT2 protein expression. Inhibition of SGLT2 prevented weight gain, reduced blood pressure, significantly reduced elevations of tyrosine hydroxylase and norepinephrine, and protects against endothelial dysfunction. These findings provide evidence for significant crosstalk between activation of the sympathetic nervous system and SGLT2 regulation and possible ancillary effects on endothelial function, which may contribute to the observed cardiorenal protective effects of SGLT2 inhibition.
| S-EPMC7046513 | biostudies-literature
Project description:Sodium-glucose co-transporter 2 (SGLT2) inhibitors, initially developed as a novel class of anti-hyperglycaemic drugs, have been shown to significantly improve metabolic indicators and protect the kidneys and heart of patients with or without type 2 diabetes mellitus. The possible mechanisms mediating these unexpected cardiorenal benefits are being extensively investigated because they cannot solely be attributed to improvements in glycaemic control. Notably, emerging data indicate that metabolic reprogramming is involved in the progression of cardiorenal metabolic diseases. SGLT2 inhibitors reprogram systemic metabolism to a fasting-like metabolic paradigm, involving the metabolic switch from carbohydrates to other energetic substrates and regulation of the related nutrient-sensing pathways, which might explain some of their cardiorenal protective effects. In this review, we will focus on the current understanding of cardiorenal protection by SGLT2 inhibitors, specifically its relevance to metabolic reprogramming.
| S-EPMC9396537 | biostudies-literature
Project description:SGLT2 inhibitors have been shown to provide pronounced reductions in cardiorenal outcomes, including cardiovascular death, heart failure, and renal failure. The mechanisms underlying these benefits remain uncertain. We hypothesized that the effects could be attributed to the elevated glycosuria induced by these drugs. Urine concentrations of glucose, creatinine, and ketones were measured at baseline and after 1 year of treatment with either placebo or canagliflozin 100 mg/day, in approximately 2,600 individuals from the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial (enrolling patients with type 2 diabetes, chronic kidney disease (CKD), and albuminuria). Associations between glycosuria and the primary composite end point from CREDENCE, and secondary outcomes were assessed using Cox proportional hazards models. Canagliflozin treatment increased fractional urinary glucose excretion (± SD) from 3 ± 9% at baseline to 30 ± 26% at year 1 (vs. 5 ± 19% with placebo; P < 0.001). Patients in the canagliflozin arm and in the top quartile of urine glucose to creatinine ratio at year 1 were significantly protected for the primary end point (hazard ratio [HR] 0.42; 95% CI 0.30-0.61); similar results were seen for cases of hospitalized heart failure (HR 0.45; 95% CI 0.27-0.73) and all-cause death (HR 0.56; 95% CI 0.39-0.80). These associations persisted when adjustments were made for multiple conventional risk factors. Among patients with type 2 diabetes and CKD treated with canagliflozin, individuals with the highest glycosuria levels had the strongest protection against multiple cardiorenal outcomes.Article highlights
| S-EPMC10796302 | biostudies-literature
Project description: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.
| S-EPMC9169967 | biostudies-literature
Project description:Sodium glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) were initially approved to improve glycemic control in the treatment of type 2 diabetes. Clinical trials have also demonstrated beneficial effects with regards to cardiovascular and renal parameters. Beyond improving glycemic control, these therapies promote weight loss and lower blood pressure when used individually, and in an additive manner when used together. Accordingly, taking advantage of complementary mechanisms of action with the combined use of these two classes of agents to further improve cardiorenal outcomes is conceptually appealing, but has yet to be explored in detail in clinical trials. In this review, we discuss proposed mechanisms for renal protection, clinical benefits, and adverse events associated with the individual and combined use of SGLT2 inhibitors and GLP-1RA. The management of type 2 diabetes has significantly changed over the last few years, moving away from solely glycemic control towards the concurrent management of associated comorbidities in a patient population at significant risk of cardiovascular disease and progression of chronic kidney disease. It is from this perspective that we seek to outline the rationale for the sequential and/or combined use of SGLT2 inhibitors and GLP-1RA in patients with type 2 diabetes.
| S-EPMC7860654 | biostudies-literature
Project description:BackgroundAngiotensin converting enzyme 2 (ACE2) has recently been identified as the functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent response for novel coronavirus disease 2019 (COVID-19). This study aimed to explore the roles of ACE2, apelin and sodium-glucose cotransporter 2 (SGLT2) in SARS-CoV-2-mediated cardiorenal damage.Methods and resultsThe published RNA-sequencing datasets of cardiomyocytes infected with SARS-CoV-2 and COVID-19 patients were used. String, UMAP plots and single cell RNA sequencing data were analyzed to show the close relationship and distinct cardiorenal distribution patterns of ACE2, apelin and SGLT2. Intriguingly, there were decreases in ACE2 and apelin expression as well as marked increases in SGLT2 and endothelin-1 levels in SARS-CoV-2-infected cardiomyocytes, animal models with diabetes, acute kidney injury, heart failure and COVID-19 patients. These changes were linked with downregulated levels of interleukin (IL)-10, superoxide dismutase 2 and catalase as well as upregulated expression of profibrotic genes and pro-inflammatory cytokines/chemokines. Genetic ACE2 deletion resulted in upregulation of pro-inflammatory cytokines containing IL-1β, IL-6, IL-17 and tumor necrosis factor α. More importantly, dapagliflozin strikingly alleviated cardiorenal fibrosis in diabetic db/db mice by suppressing SGLT2 levels and potentiating the apelin-ACE2 signaling.ConclusionDownregulation of apelin and ACE2 and upregulation of SGLT2, endothelin-1 and pro-inflammatory cytokines contribute to SARS-CoV-2-mediated cardiorenal injury, indicating that the apelin-ACE2 signaling and SGLT2 inhibitors are potential therapeutic targets for COVID-19 patients.
| S-EPMC8123373 | biostudies-literature
Project description:The objective of the present study is to explore the role of human MSC derived adipocytes transduced with/without lenti adipo-NaKtide or lenti adipo-scrambled NaKtide in experimental uremic cardiomyopathy. We investigated the pathophysiological changes in recipient mice that underwent partial nephrectomy surgery, as a model of uremic cardiomyopathy, and implanted with NaKtide transfected human MSC derived adipocytes. We aimed to demonstrate that adipocyte specific NaKtide reprograms the adipocyte phenotype and transplantation of these metabolically healthy adipocytes in diseased condition exhibits improved systemic and cardiovascular function, through intra-organ crosstalk.
2023-04-05 | GSE200328 | GEO
Project description:Cardiotonic steroids (such as ouabain) signaling through Na/K-ATPase regulate sodium reabsorption in the renal proximal tubule. We report here that reactive oxygen species are required to initiate ouabain-stimulated Na/K-ATPase·c-Src signaling. Pretreatment with the antioxidant N-acetyl-L-cysteine prevented ouabain-stimulated Na/K-ATPase·c-Src signaling, protein carbonylation, redistribution of Na/K-ATPase and sodium/proton exchanger isoform 3, and inhibition of active transepithelial (22)Na(+) transport. Disruption of the Na/K-ATPase·c-Src signaling complex attenuated ouabain-stimulated protein carbonylation. Ouabain-stimulated protein carbonylation is reversed after removal of ouabain, and this reversibility is largely independent of de novo protein synthesis and degradation by either the lysosome or the proteasome pathways. Furthermore, ouabain stimulated direct carbonylation of two amino acid residues in the actuator domain of the Na/K-ATPase ?1 subunit. Taken together, the data indicate that carbonylation modification of the Na/K-ATPase ?1 subunit is involved in a feed-forward mechanism of regulation of ouabain-mediated renal proximal tubule Na/K-ATPase signal transduction and subsequent sodium transport.
| S-EPMC3837165 | biostudies-literature
Project description:Over the last 5 years there have been many new developments in the management of diabetic kidney disease. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 (SGLT2) inhibitors were initially used for glycemic control, but more recent studies have now shown that their benefits extend to cardiovascular and kidney outcomes. The recent addition of data on the novel mineralocorticoid receptor antagonist (MRA) gives us another approach to further decrease the residual risk of diabetic kidney disease progression. In this review we describe the mechanism of action, key studies, and possible adverse effects related to these three classes of medications. The management of type 2 diabetes now includes an increasing number of medications for the management of comorbidities in a patient population at significant risk of cardiovascular disease and progression of chronic kidney disease. It is from this perspective that we seek to outline the rationale for the sequential and/or combined use of SGLT2 inhibitors, GLP-1 RA and MRAs in patients with type 2 diabetes for heart and kidney protection.
| S-EPMC8090466 | biostudies-literature
Project description:Type 2 diabetes mellitus (T2DM) is a growing public health concern worldwide. Numerous drug classes are available for treatment, however, their efficacy with regard to diabetes-induced renal and cardiovascular (CV) complications remains limited. Inhibitors of the sodium-glucose cotransporter 2 (SGLT2) are a new class of blood glucose lowering medications that block renal glucose reabsorption and have protective effects on the kidney and the heart. This review focusses on the effects of SGLT2 inhibitors on the kidney and renal outcome: it briefly outlines renal glucose handling in diabetes and its role in glomerular hyperfiltration and renal hypoxia; describes how SGLT2 inhibitors induce an early, reversible reduction in glomerular filtration rate (GFR) and preserve GFR in the long-term in patients with T2DM; discusses whether the enhanced active transport in the renal outer medulla (OM) in response to SGLT2 inhibition is friend or foe; proposes how the blood pressure lowering and heart failure protective effect of SGLT2 inhibitors can be preserved in chronic kidney disease (CKD) despite attenuated antihyperglycemic effects; and examines whether SGLT2 inhibition enhances the incidence or severity of acute kidney injury (AKI).
| S-EPMC6648703 | biostudies-literature