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

Abstract

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.

Angiotensin II reduces glyoxalase 1 activity and expression in vascular smooth muscle cells: Implications for diabetic vascular complications

“…This excessive glycolytic activity results in enhanced MGO concentration 46 . Inducing ERK1/2 MAPK with SGLT2 inhibitors has the potential to promote an increase in Glo1 activity and a decrease in MGO concentration, as it has been recognized as a crucial element within the cardioprotective pathway that mitigates damage during reperfusion 43 . However, empagliflozin pretreatment prevents severe fatal ventricular arrhythmia, likely through glucose‐independent ERK1/2 activation 47 .…”

“…Consequently, this inhibition contributes to decreased formation and progression of atherosclerotic plaques. 43,44 In lipopolysaccharidestimulated human coronary artery endothelial cells, it is noteworthy that canagliflozin, as opposed to empagliflozin or dapagliflozin, effectively mitigates inflammation and reduces hexokinase II expression. This reduction is achieved through the inhibition of ERK1/2 phosphorylation.…”

“…46 Inducing ERK1/2 MAPK with SGLT2 inhibitors has the potential to promote an increase in Glo1 activity and a decrease in MGO concentration, as it has been recognized as a crucial element within the cardioprotective pathway that mitigates damage during reperfusion. 43 However, empagliflozin pretreatment prevents severe fatal ventricular arrhythmia, likely through glucose-independent ERK1/2 activation. 47 The potential of SGLT2 inhibitors to enhance Glo1 expression by inhibiting ERK1/2 and p38 MAPKs warrants further investigation.…”

New Insight in Cardiorenal Syndrome: From Biomarkers to Therapy

“…SGLT2is have an excellent diuretic and metabolic effect, as well as they may exert several other mechanisms, including neurohormonal modulation and reducing oxidative stress, inflammation and cardiovascular remodeling [ 172 ] ( Figure 2 ). Experimental and clinical studies have demonstrated an excellent nephroprotective effect for this class of drugs, even stronger than that shown by ACEi or ARBs, which are considered the most effective drugs for preserving kidney function in HF patients [ 173 , 174 ].…”

Personalized Management for Heart Failure with Preserved Ejection Fraction

“…Accordingly, HFpEF can be classified into different phenotypes based on various criteria, including underlying etiology, clinical characteristics, and comorbidities [ 3 , 4 , 5 , 6 , 7 , 8 ]. Detailed molecular signaling, gene ontology functional analysis, and the use of the Kyoto Encyclopedia of Genes and Genomes pathway also potentiate the precise mechanisms of action and targets of SGLT2 inhibitors in clinical practice [ 9 , 10 ]. A comprehensive understanding and the specific pathways identified from HFpEF phenotyping also facilitate animal experimental studies to address relevant pathophysiological signaling [ 11 ].…”