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

Anzhu Wang; Zhendong Li; Sun Zhuo; Feng Gao; Hongwei Zhang; Zhibo Zhang; Gaocan Ren; Xiaochang Ma

doi:10.3389/fcvm.2022.857952

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

Front Cardiovasc Med. 2022 May 23:9:857952. doi: 10.3389/fcvm.2022.857952. eCollection 2022.

Authors

Anzhu Wang^{1

2}, Zhendong Li³, Sun Zhuo³, Feng Gao^{1

2}, Hongwei Zhang^{1

2}, Zhibo Zhang^{1

4}, Gaocan Ren^{1

2}, Xiaochang Ma^{1

5}

Affiliations

¹ Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
² Graduate School, China Academy of Chinese Medical Sciences, Beijing, China.
³ Qingdao West Coast New Area People's Hospital, Qingdao, China.
⁴ Beijing University of Chinese Medicine, Beijing, China.
⁵ Clinical Research Center for Chinese Medicine Cardiology, Beijing, China.

Abstract

Purpose: Sodium-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 methods: We 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.

Results: Seven 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.

Conclusion: Based 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.

Keywords: cardiorenal protection; chronic kidney disease; heart failure; sodium-glucose cotransporter 2 inhibitors; type 2 diabetes mellitus.